ORCID Profile
0000-0002-8539-4891
Current Organisation
University of Melbourne
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Nanotechnology | Nanobiotechnology | Synthesis of Materials | Nanomaterials | Nanotechnology | Biomedical Engineering | Nanomedicine | Immunology | Colloid And Surface Chemistry | Immunology Not Elsewhere Classified | Pharmaceutical Sciences | Optical Physics Not Elsewhere Classified | Functional Materials | Virology | Medical Virology | Medical Bacteriology | Dynamical Systems | Biomaterials | Biomechanical Engineering | Biomaterials | Physical Chemistry (Incl. Structural) | Biotechnology Not Elsewhere Classified | Infectious Diseases | Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Clinical Sciences | Humoral Immunology And Immunochemistry | Medical Virology | Tumour Immunology | Cellular Immunology | Autoimmunity |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Cancer and Related Disorders | Prevention—biologicals (e.g. vaccines) | Infectious diseases | Expanding Knowledge in Technology | Expanding Knowledge in Engineering | Inherited Diseases (incl. Gene Therapy) | Biological sciences | Diabetes | Blood Disorders | Diagnostics | Immune System and Allergy | Infectious Diseases | Immune system and allergy | Expanding Knowledge in the Medical and Health Sciences | Scientific instrumentation | Diagnostic Methods | Prevention—biologicals (e.g. vaccines) | Diagnostics | Treatments (e.g. chemicals, antibiotics)
Related Links
Publications
Role of IgG3 in Infectious Diseases
Publisher: Elsevier BV
Date: 03-2019
Abstract: IgG3 comprises only a minor fraction of IgG and has remained relatively understudied until recent years. Key physiochemical characteristics of IgG3 include an elongated hinge region, greater molecular flexibility, extensive polymorphisms, and additional glycosylation sites not present on other IgG subclasses. These characteristics make IgG3 a uniquely potent immunoglobulin, with the potential for triggering effector functions including complement activation, antibody (Ab)-mediated phagocytosis, or Ab-mediated cellular cytotoxicity (ADCC). Recent studies underscore the importance of IgG3 effector functions against a range of pathogens and have provided approaches to overcome IgG3-associated limitations, such as allotype-dependent short Ab half-life, and excessive proinflammatory activation. Understanding the molecular and functional properties of IgG3 may facilitate the development of improved Ab-based immunotherapies and vaccines against infectious diseases.
Block and Lock HIV Cure Strategies to Control the Latent Reservoir
Publisher: Frontiers Media SA
Date: 14-08-2020
Evaluation of recombinant Kunjin replicon SIV vaccines for protective efficacy in macaques
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.VIROL.2008.01.006
Abstract: Persistent gag-specific T cell immunity would be a useful component of an effective HIV vaccine. The Flavivirus Kunjin replicon was previously engineered to persistently express HIV gag and was shown to induce protective responses in mice. We evaluated Kunjin replicon virus-like-particles expressing SIVgag-pol in pigtail macaques. Kunjin-specific antibodies were induced, but no SIV-specific T cell immunity were detected. Following SIVmac251 challenge, there was no difference in SIV viremia or retention of CD4 T cells between Kunjin-SIVgag-pol vaccine immunized animals and controls. An amnestic SIV gag-specific CD8 T cell response associated with control of viremia was observed in 1 of 6 immunized animals. Refinements of this vector system and optimization of the immunization doses, routes, and schedules are required prior to clinical trials.
Twist in the Tail: Escape from HIV Neutralising Antibodies at a Single Site Confers Broad Susceptibility to Others.
Publisher: Elsevier BV
Date: 10-2016
Perturbation of mucosal-associated invariant T cells and iNKT cells in HIV infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
Differential Roles of Plasma Protein Corona on Immune Cell Association and Cytokine Secretion of Oligomeric and Fibrillar Beta-Amyloid.
Publisher: American Chemical Society (ACS)
Date: 10-10-2019
Low‐Fouling Fluoropolymers for Bioconjugation and In Vivo Tracking
Publisher: Wiley
Date: 03-02-2020
Abstract: The conjugation of hydrophilic low-fouling polymers to therapeutic molecules and particles is an effective approach to improving their aqueous stability, solubility, and pharmacokinetics. Recent concerns over the immunogenicity of poly(ethylene glycol) has highlighted the importance of identifying alternative low fouling polymers. Now, a new class of synthetic water-soluble homo-fluoropolymers are reported with a sulfoxide side-chain structure. The incorporation of fluorine enables direct imaging of the homopolymer by
Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - New technologies and their impact on the HIV vaccine field
Publisher: Bentham Science Publishers Ltd.
Date: 03-07-2017
CD127+CCR5+CD38+++CD4+Th1 Effector Cells Are an Early Component of the Primary Immune Response to Vaccinia Virus and Precede Development of Interleukin-2
Publisher:
American Society for Microbiology
Date:
15-10-2006
DOI:
10.1128/JVI.02670-05
Abstract: The stages of development of human antigen-specific CD4 + T cells responding to viral infection and their differentiation into long-term memory cells are not well understood. The inoculation of healthy adults with vaccinia virus presents an opportunity to study these events intensively. Between days 11 and 14 postinoculation, there was a peak of proliferating CCR5 + CD38 +++ CD4 + effector cells which contained the cytotoxic granule marker T-cell intracellular antigen 1 and included gamma interferon (IFN-γ)-producing vaccinia virus-specific CD4 + T cells. The majority of these initial vaccinia virus-specific CD4 + T cells were CD127 + and produced interleukin-2 (IL-2) but not CTLA-4 in response to restimulation in vitro. Between days 14 and 21, there was a switch from IFN-γ and IL-2 coexpression to IL-2 production only, coinciding with a resting phenotype and an increased in vitro proliferation response. The early CCR5 + CD38 +++ vaccinia virus-specific CD4 + T cells were similar to our previous observations of human immunodeficiency virus (HIV)-specific CD4 + T cells in primary HIV type 1 (HIV-1) infection, but the vaccinia virus-specific cells expressed much more CD127 and IL-2 than we previously found in their HIV-specific counterparts. The current study provides important information on the differentiation of IL-2 + vaccinia virus-specific memory cells, allowing further study of antiviral effector CD4 + T cells in healthy adults and their dysfunction in HIV-1 infection.
Publisher: American Society for Microbiology
Date: 15-10-2006
DOI: 10.1128/JVI.02670-05
Abstract: The stages of development of human antigen-specific CD4 + T cells responding to viral infection and their differentiation into long-term memory cells are not well understood. The inoculation of healthy adults with vaccinia virus presents an opportunity to study these events intensively. Between days 11 and 14 postinoculation, there was a peak of proliferating CCR5 + CD38 +++ CD4 + effector cells which contained the cytotoxic granule marker T-cell intracellular antigen 1 and included gamma interferon (IFN-γ)-producing vaccinia virus-specific CD4 + T cells. The majority of these initial vaccinia virus-specific CD4 + T cells were CD127 + and produced interleukin-2 (IL-2) but not CTLA-4 in response to restimulation in vitro. Between days 14 and 21, there was a switch from IFN-γ and IL-2 coexpression to IL-2 production only, coinciding with a resting phenotype and an increased in vitro proliferation response. The early CCR5 + CD38 +++ vaccinia virus-specific CD4 + T cells were similar to our previous observations of human immunodeficiency virus (HIV)-specific CD4 + T cells in primary HIV type 1 (HIV-1) infection, but the vaccinia virus-specific cells expressed much more CD127 and IL-2 than we previously found in their HIV-specific counterparts. The current study provides important information on the differentiation of IL-2 + vaccinia virus-specific memory cells, allowing further study of antiviral effector CD4 + T cells in healthy adults and their dysfunction in HIV-1 infection.
Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy
Publisher: American Society for Microbiology
Date: 02-2009
DOI: 10.1128/JVI.02119-08
Abstract: Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIV mac251 infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4 + T-cell responses (mean, 5.9% ± 1.3% of all CD4 + T cells) and to a lesser extent SIV-specific CD8 + T-cell responses (mean, 0.7% ± 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4 + T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4 + T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide-pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted.
Induction of T-cell immunity to antiretroviral drug-resistant human immunodeficiency virus type 1
Publisher: American Society for Microbiology
Date: 15-06-2005
DOI: 10.1128/JVI.79.12.7728-7737.2005
Abstract: Antiretroviral drug-resistant human immunodeficiency virus type 1 (HIV-1) is a major, growing, public health problem. Immune responses targeting epitopes spanning drug resistance sites could ameliorate development of drug resistance. We studied 25 in iduals harboring multidrug-resistant HIV-1 for T-cell immunity to HIV-1 proteins and peptides spanning all common drug resistance mutations. CD8 T cells targeting epitopes spanning drug-induced mutations were detected but only in the 3 in iduals with robust HIV-specific T-cell activity. Novel CD8 T-cell responses were detected against the common L63P and L10I protease inhibitor fitness mutations. Induction of T-cell immunity to drug-resistant variants was demonstrated in simian human immunodeficiency virus-infected macaques, where both CD8 and CD4 T-cell immune responses to reverse transcriptase and protease antiretroviral mutations were elicited using a novel peptide-based immunotherapy. T-cell responses to antiretroviral resistance mutations were strongest in the most immunocompetent animals. This study suggests feasible strategies to further evaluate the potential of limiting antiretroviral drug resistance through induction of T-cell immunity.
Robust correlations across six SARS‐CoV‐2 serology assays detecting distinct antibody features
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1258
Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-08-2017
DOI: 10.1126/SCITRANSLMED.AAF1483
Abstract: Broadly neutralizing antibody confers partial protection from cell-associated SHIV.
Linking pig-tailed macaque major histocompatibility complex class I haplotypes and cytotoxic T lymphocyte escape mutations in simian immunodeficiency virus infection.
Publisher: American Society for Microbiology
Date: 15-12-2014
DOI: 10.1128/JVI.02428-14
Abstract: The influence of major histocompatibility complex class I (MHC-I) alleles on human immunodeficiency virus (HIV) ersity in humans has been well characterized at the population level. MHC-I alleles likely affect viral ersity in the simian immunodeficiency virus (SIV)-infected pig-tailed macaque ( Macaca nemestrina ) model, but this is poorly characterized. We studied the evolution of SIV in pig-tailed macaques with a range of MHC-I haplotypes. SIV mac251 genomes were lified from the plasma of 44 pig-tailed macaques infected with SIV mac251 at 4 to 10 months after infection and characterized by Illumina deep sequencing. MHC-I typing was performed on cellular RNA using Roche/454 pyrosequencing. MHC-I haplotypes and viral sequence polymorphisms at both in idual mutations and groups of mutations spanning 10-amino-acid segments were linked using in-house bioinformatics pipelines, since cytotoxic T lymphocyte (CTL) escape can occur at different amino acids within the same epitope in different animals. The approach successfully identified 6 known CTL escape mutations within 3 Mane-A1*084-restricted epitopes. The approach also identified over 70 new SIV polymorphisms linked to a variety of MHC-I haplotypes. Using functional CD8 T cell assays, we confirmed that one of these associations, a Mane-B028 haplotype-linked mutation in Nef, corresponded to a CTL epitope. We also identified mutations associated with the Mane-B017 haplotype that were previously described to be CTL epitopes restricted by Mamu-B*017:01 in rhesus macaques. This detailed study of pig-tailed macaque MHC-I genetics and SIV polymorphisms will enable a refined level of analysis for future vaccine design and strategies for treatment of HIV infection. IMPORTANCE Cytotoxic T lymphocytes select for virus escape mutants of HIV and SIV, and this limits the effectiveness of vaccines and immunotherapies against these viruses. Patterns of immune escape variants are similar in HIV type 1-infected human subjects that share the same MHC-I genes, but this has not been studied for SIV infection of macaques. By studying SIV sequence ersity in 44 MHC-typed SIV-infected pigtail macaques, we defined over 70 sites within SIV where mutations were common in macaques sharing particular MHC-I genes. Further, pigtail macaques sharing nearly identical MHC-I genes with rhesus macaques responded to the same CTL epitope and forced immune escape. This allows many reagents developed to study rhesus macaques to also be used to study pigtail macaques. Overall, our study defines sites of immune escape in SIV in pigtailed macaques, and this enables a more refined level of analysis of future vaccine design and strategies for treatment of HIV infection.
Vaccines for HIV in the developing world
Publisher: Wiley
Date: 04-2002
Rapid Viral Escape at an Immunodominant Simian-Human Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitope Exacts a Dramatic Fitness Cost
Publisher: American Society for Microbiology
Date: 05-2005
DOI: 10.1128/JVI.79.9.5721-5731.2005
Abstract: Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched in iduals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIV SF162P3 . Another challenge virus, SHIV mn229 , previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.
Toward Improved Influenza Vaccines
Publisher: Oxford University Press (OUP)
Date: 17-10-2013
Efficacy of DNA and fowlpox virus priming/boosting vaccines for simian/human immunodeficiency virus
Publisher: American Society for Microbiology
Date: 15-12-2004
DOI: 10.1128/JVI.78.24.13819-13828.2004
Abstract: Further advances are required in understanding protection from AIDS by T-cell immunity. We analyzed a set of multigenic simian/human immunodeficiency virus (SHIV) DNA and fowlpox virus priming and boosting vaccines for immunogenicity and protective efficacy in outbred pigtail macaques. The number of vaccinations required, the effect of DNA vaccination alone, and the effect of cytokine (gamma interferon) coexpression by the fowlpox virus boost was also studied. A coordinated induction of high levels of broadly reactive CD4 and CD8 T-cell immune responses was induced by sequential DNA and fowlpox virus vaccination. The immunogenicity of regimens utilizing fowlpox virus coexpressing gamma interferon, a single DNA priming vaccination, or DNA vaccines alone was inferior. Significant control of a virulent SHIV challenge was observed despite a loss of SHIV-specific proliferating T cells. The outcome of challenge with virulent SHIV mn229 correlated with vaccine immunogenicity except that DNA vaccination alone primed for protection almost as effectively as the DNA/fowlpox virus regimen despite negligible immunogenicity by standard assays. These studies suggest that priming of immunity with DNA and fowlpox virus vaccines could delay AIDS in humans.
Thrombocytopenia is strongly associated with simian AIDS in pigtail macaques
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2009
Role of education and differentiation in determining the potential of natural killer cells to respond to antibody-dependent stimulation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-11-2014
P17-03. Nanoengineered layer-by-layer capsules as a novel delivery system for HIV vaccines
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Mucosal and systemic SIV-specific cytotoxic CD4+ T cell hierarchy in protection following intranasal/intramuscular recombinant pox-viral vaccination of pigtail macaques
Publisher: Springer Science and Business Media LLC
Date: 05-04-2019
DOI: 10.1038/S41598-019-41506-5
Abstract: A HIV vaccine that provides mucosal immunity is urgently needed. We evaluated an intranasal recombinant Fowlpox virus (rFPV) priming vaccine followed by intramuscular Modified Vaccinia Ankara (rMVA) booster vaccine, both expressing SIV antigens. The vaccination generated mucosal and systemic SIV-specific CD4 + T cell mediated immunity and was associated with partial protection against high-dose intrarectal SIV mac251 challenge in outbred pigtail macaques. Three of 12 vaccinees were completely protected and these animals elicited sustained Gag-specific poly-functional, cytotoxic mucosal CD4 + T cells, complemented by systemic poly-functional CD4 + and CD8 + T cell immunity. Humoral immune responses, albeit absent in completely protected macaques, were associated with partial control of viremia in animals with relatively weaker mucosal/systemic T cell responses. Co-expression of an IL-4R antagonist by the rFPV vaccine further enhanced the breadth and cytotoxicity oly-functionality of mucosal vaccine-specific CD4 + T cells. Moreover, a single FPV- gag ol/env prime was able to induce rapid anamnestic gp140 antibody response upon SIV encounter. Collectively, our data indicated that nasal vaccination was effective at inducing robust cervico-vaginal and rectal immunity, although cytotoxic CD4 + T cell mediated mucosal and systemic immunity correlated strongly with ‘complete protection’, the different degrees of protection observed was multi-factorial.
Nice and slow make the germinal centers go: measured and escalating antigen delivery enhance durability and quality of humoral immune responses against HIV‐1
Publisher: Wiley
Date: 31-10-2022
DOI: 10.1111/IMCB.12596
Abstract: A recently published article has confirmed that a novel immunization method of sustained and escalating antigen delivery augments the magnitude, quality and durability of humoral immune responses.
From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases
Publisher: Elsevier BV
Date: 09-2021
High CD26 and Low CD94 Expression Identifies an IL-23 Responsive Vδ2+ T Cell Subset with a MAIT Cell-like Transcriptional Profile
Publisher: Elsevier BV
Date: 06-2020
Influence of charge on hemocompatibility and immunoreactivity of polymeric nanoparticles
Publisher: American Chemical Society (ACS)
Date: 05-09-2018
Boosting of Markers of Fcγ Receptor Function in Anti-HIV Antibodies During Structured Treatment Interruption.
Publisher: Mary Ann Liebert Inc
Date: 09-2019
The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-10-2007
DOI: 10.1002/HEP.21844
Abstract: Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from in iduals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8(+) T cells from the liver producing IL-10 (P = 0.044), primarily in hepatitis B e antigen positive (HBeAg(+)) in iduals. A positive correlation resulted between the magnitude of HBV-specific TNF-alpha(+) CD4(+) T cells in the liver and the degree of liver inflammation and fibrosis (P = 0.002 and P = 0.006, respectively). The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.
The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a randomised, placebo-controlled, double-blind trial.
Publisher: Elsevier BV
Date: 05-2018
Differential patterns of immune escape at Tat-specific cytotoxic T cell epitopes in pigtail macaques
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.VIROL.2009.03.020
Abstract: Cytotoxic T lymphocyte responses to conserved proteins such as Gag within HIV- or SIV-infected hosts can facilitate partial control of viremia. However, the utility of targeting variable viral proteins by CTL responses is unclear. We studied CTL responses to regulatory and accessory proteins of SIV in pigtail macaques. The regulatory and accessory proteins were the most commonly targeted proteins by CTL responses from pigtail macaques. We identified 2 novel Tat-specific CTL responses that were both restricted by the Mane-A10 allele. Viral escape at one of the Tat epitopes, KSA10, was slower in comparison to another Tat epitope KVA10. The kinetics of escape of the KSA10 Tat epitope were more similar to an immunodominant KP9 Gag epitope also restricted by Mane-A10. Our results suggest that some regulatory or accessory CTL epitopes may be useful targets for vaccination against HIV.
Modulation of the CCR5 Receptor/Ligand Axis by Seminal Plasma and the Utility of In Vitro versus In Vivo Models
Publisher: American Society for Microbiology
Date: 06-2019
DOI: 10.1128/JVI.00242-19
Abstract: The majority of HIV-1 vaccine studies do not take into consideration the impact that semen exposure might have on the mucosal immune system. In this study, we demonstrate that seminal plasma (SP) exposure can alter CCR5 expression on T cells. Importantly, in vitro studies of T cells in culture cannot replicate the conditions under which immune cells might be recruited to the genital mucosa in vivo , leading to potentially erroneous conclusions about the impact of semen on mucosal HIV-1 susceptibility.
Identification of native and posttranslationally modified HLA-B*57:01- restricted HIV envelope derived epitopes using immunoproteomics
Publisher: Wiley
Date: 10-04-2018
Abstract: The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified. HIVenv peptides are present at a very small percentage of the overall HLA-B*57:01 peptidome (<0.1%) and both native and posttranslationally modified forms of two distinct HIV peptides are identified. Notably, a peptide bearing a natively encoded C-terminal tryptophan residue is also present in a modified form containing a kynurenine residue. Kynurenine is a major product of tryptophan catabolism and is abundant during inflammation and infection. Binding of these peptides at a molecular level and their immunogenicity in preliminary functional studies are examined. Modest immune responses are observed to the modified HIVenv peptide, highlighting a potential role for kynurenine-modified peptides in the immune response to HIV and other viral infections.
Controlling the Biological Fate of Micellar Nanoparticles: Balancing Stealth and Targeting
Publisher: American Chemical Society (ACS)
Date: 16-09-2020
Comparative efficacy of subtype AE simian-human immunodeficiency virus priming and boosting vaccines in pigtail macaques
Publisher: American Society for Microbiology
Date: 2007
DOI: 10.1128/JVI.01727-06
Abstract: Vaccination against AIDS is h ered by great ersity between human immunodeficiency virus (HIV) strains. Heterologous B-subtype-based simian-human immunodeficiency virus (SHIV) DNA prime and poxvirus boost vaccine regimens can induce partial, T-cell-mediated, protective immunity in macaques. We analyzed a set of DNA, recombinant fowlpox viruses (FPV), and vaccinia viruses (VV) expressing subtype AE HIV type 1 (HIV-1) Tat, Rev, and Env proteins and SIV Gag/Pol in 30 pigtail macaques. SIV Gag-specific CD4 and CD8 T-cell responses were induced by sequential DNA/FPV vaccination, although lower FPV doses, VV/FPV vaccination, and DNA vaccines alone were not as consistently immunogenic. The SHIV AE DNA prime, FPV boost regimens were significantly less immunogenic than comparable B-subtype SHIV vaccination. Peak viral load was modestly (0.4 log 10 copies/ml) lower among the AE subtype SHIV-immunized animals compared to controls following the virulent B subtype SHIV challenge. Protection from persistent high levels of viremia and CD4 T-cell depletion was less in AE subtype compared to B subtype SHIV-vaccinated macaques. Gag was highly immunodominant over the other AE subtype SHIV vaccine proteins after vaccination, and this immunodominance was exacerbated after challenge. Interestingly, the lower level of priming of immune responses did not blunt postchallenge Gag-specific recall responses, despite more modest protection. These studies suggest priming of T-cell immunity to prevent AIDS in humans is possible, but differences in the immunogenicity of various subtype vaccines and broad cross-subtype protection are substantial hurdles.
Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria.
Publisher: eLife Sciences Publications, Ltd
Date: 29-06-2021
DOI: 10.7554/ELIFE.65776
Abstract: Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum -infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria. We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea. The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria. We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria. This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).
Exploration of broadly neutralizing antibody fragments produced in bacteria for the control of HIV
Publisher: Informa UK Limited
Date: 26-09-2017
A randomized, placebo-controlled phase I trial of DNA prime, recombinant fowlpox virus boost prophylactic vaccine for HIV-1
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-01-2006
Characterisation of simian immunodeficiency virus-infected cells in pigtail macaques
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.VIROL.2012.03.016
Abstract: Defining which cells become infected with simian immunodeficiency virus (SIV) in vivo should assist in unravelling the pathogenesis of human immunodeficiency virus (HIV)/SIV infection. HIV/SIV infection of CD4(+) T cells resulted in down-regulation of CD3 and CD4 surface molecules in vitro, however this phenomenon is poorly characterised in vivo. Intracellular SIV p27 was studied by flow cytometry in serial blood s les and lymph node s les during acute infection of 17 SIVmac-infected pigtail macaques. Two weeks after infection, a mean of 56±6.8% the p27(+) cells were lymphocytes negative for surface CD4 and CD3, and indeed the highest proportion of SIV infected cells were found in the small subset of CD3(Lo)CD4(-)CD8(-) lymphocytes, indicating that infection has lead to down-regulation of these markers in vivo. Furthermore, the relative amount of SIV p27 within lymphocytes (based of mean fluorescence intensity) was higher in CD3(Lo)CD4(-) and CD3(-) infected cells than in CD3(+) or CD4(+) p27(+) populations, consistent with greater viral production in CD4(+) T cells down-regulating CD3 and CD4 molecules. The CD3(-)CD4(-) infected cells expressed T cell markers CD2 and CD5 and were negative for monocyte, NK and B cell markers. The majority of infected cells were CD28(+)CD95(+) central memory T cells. Surprisingly, p27(+) blood lymphocytes were mostly negative for activation markers CD25 and CD69, but most of the infected lymph nodes cells were activated. Our results characterise productively-infected macaque lymphocytes in vivo. The high proportion of SIV-infected lymphocytes that are CD3(-)CD4(-) has important implications for the in vivo study of pathogenesis of SIV/HIV infections.
Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies
Publisher: The American Association of Immunologists
Date: 15-02-2013
Abstract: A better understanding of immunity to influenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemokines. ADCC Abs may target more conserved influenza virus Ags compared with neutralizing Abs. There has been minimal interest in influenza-specific ADCC in recent decades. In this study, we developed novel assays to assess the specificity and function of influenza-specific ADCC Abs. We found that healthy influenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 influenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and in vitro elimination of influenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 influenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivity of influenza-specific ADCC Abs in seropositive humans. Targeting cross-reactive influenza-specific ADCC epitopes by vaccination could lead to improved influenza vaccines.
Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation
Publisher: American Society for Clinical Investigation
Date: 21-05-2020
The role of T cell immunity in HIV-1 infection
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.COVIRO.2013.05.009
Abstract: The interplay between the T cell immune response and human immunodeficiency virus (HIV)-1 largely determines the outcome of infection. Typically, the virus overcomes the immune defences leading to a gradual decline in function that permits the development of disease. In recent years, a concerted effort in comparing T cell responses between 'controllers' and 'progressors' is beginning to identify the T cell subsets and factors that affect disease progression related to the effector functions of both CD4 and CD8 T cells. These efforts are providing opportunities for development of novel therapies and vaccines.
Expanding role for type I Interferons in restricting HIV growth
Publisher: Wiley
Date: 25-04-2017
DOI: 10.1038/ICB.2017.15
In-vivo stimulation of macaque natural killer T cells with α-galactosylceramide
Publisher: Oxford University Press (OUP)
Date: 06-08-2013
DOI: 10.1111/CEI.12132
Abstract: Natural killer T cells are a potent mediator of anti-viral immunity in mice, but little is known about the effects of manipulating NKT cells in non-human primates. We evaluated the delivery of the NKT cell ligand, α-galactosylceramide (α-GalCer), in 27 macaques by studying the effects of different dosing (1–100 μg), and delivery modes [directly intravenously (i.v.) or pulsed onto blood or peripheral blood mononuclear cells]. We found that peripheral NKT cells were depleted transiently from the periphery following α-GalCer administration across all delivery modes, particularly in doses of ≥10 μg. Furthermore, NKT cell numbers frequently remained depressed at i.v. α-GalCer doses of & μg. Levels of cytokine expression were also not enhanced after α-GalCer delivery to macaques. To evaluate the effects of α-GalCer administration on anti-viral immunity, we administered α-GalCer either together with live attenuated influenza virus infection or prior to simian immunodeficiency virus (SIV) infection of two macaques. There was no clear enhancement of influenza-specific T or B cell immunity following α-GalCer delivery. Further, there was no modulation of pathogenic SIVmac251 infection following α-GalCer delivery to a further two macaques in a pilot study. Accordingly, although macaque peripheral NKT cells are modulated by α-GalCer in vivo, at least for the dosing regimens tested in this study, this does not appear to have a significant impact on anti-viral immunity in macaque models.
SARS‐CoV‐2‐specific CD8+ T‐cell responses and TCR signatures in the context of a prominent HLA‐A*24:02 allomorph
Publisher: Wiley
Date: 30-06-2021
DOI: 10.1111/IMCB.12482
Abstract: In‐depth understanding of human T‐cell‐mediated immunity in coronavirus disease 2019 (COVID‐19) is needed if we are to optimize vaccine strategies and immunotherapies. Identification of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) T‐cell epitopes and generation of peptide–human leukocyte antigen (peptide–HLA) tetramers facilitate direct ex vivo analyses of SARS‐CoV‐2‐specific T cells and their T‐cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARS‐CoV‐2 epitopes restricted by HLA‐A*24:02, one of the most prominent HLA class I alleles, especially in Indigenous and Asian populations. Of the peptides screened, three spike‐derived peptides generated CD8 + IFNγ + responses above background, S 1208–1216 (QYIKWPWYI), S 448–456 (NYNYLYRLF) and S 193–201 (VFKNIDGYF), with S 1208 generating immunodominant CD8 + IFNγ + responses. Using peptide–HLA‐I tetramers, we performed direct ex vivo tetramer enrichment for HLA‐A*24:02‐restricted CD8 + T cells in COVID‐19 patients and prepandemic controls. The precursor frequencies for HLA‐A*24:02‐restricted epitopes were within the range previously observed for other SARS‐CoV‐2 epitopes for both COVID‐19 patients and prepandemic in iduals. Naïve A24/SARS‐CoV‐2‐specific CD8 + T cells increased nearly 7.5‐fold above the average precursor frequency during COVID‐19, gaining effector and memory phenotypes. Ex vivo single‐cell analyses of TCRαβ repertoires found that the A24/S 448 + CD8 + T‐cell TCRαβ repertoire was driven by a common TCRβ chain motif, whereas the A24/S 1208 + CD8 + TCRαβ repertoire was erse across COVID‐19 patients. Our study provides an in depth characterization and important insights into SARS‐CoV‐2‐specific CD8 + T‐cell responses associated with a prominent HLA‐A*24:02 allomorph. This contributes to our knowledge on adaptive immune responses during primary COVID‐19 and could be exploited in vaccine or immunotherapeutic approaches.
A point-of-care lateral flow assay for neutralising antibodies against SARS-CoV-2
Publisher: Elsevier BV
Date: 12-2021
Sequencing B cell receptors from ferrets (Mustela putorius furo)
Publisher: Public Library of Science (PLoS)
Date: 29-05-2020
Defining the objectives of the AIDS vaccine for Asia network: report of the WHO-UNAIDS/Global HIV vaccine enterprise regional consultation on expanding AIDS vaccine research and development capacity i
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2010
Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine
Publisher: Cold Spring Harbor Laboratory
Date: 10-01-2022
DOI: 10.1101/2022.01.08.22268953
Abstract: Humans commonly have low level antibodies to poly(ethylene) glycol (PEG) due to environmental exposure. Lipid nanoparticle (LNP) mRNA vaccines for SARS-CoV-2 contain small amounts of PEG but it is not known whether PEG antibodies are enhanced by vaccination and what their impact is on particle–immune cell interactions in human blood. We studied plasma from 130 adults receiving either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) mRNA vaccines, or no SARS-CoV-2 vaccine for PEG-specific antibodies. Anti-PEG IgG was commonly detected prior to vaccination and was significantly boosted a mean of 13.1-fold (range 1.0 to 70.9) following mRNA-1273 vaccination and a mean of 1.78-fold (range 0.68 to 16.6) following BNT162b2 vaccination. Anti-PEG IgM increased 68.5-fold (range 0.9 to 377.1) and 2.64-fold (0.76 to 12.84) following mRNA-1273 and BNT162b2 vaccination, respectively. The rise in PEG-specific antibodies following mRNA-1273 vaccination was associated with a significant increase in the association of clinically relevant PEGylated LNPs with blood phagocytes ex vivo . PEG antibodies did not impact the SARS-CoV-2 specific neutralizing antibody response to vaccination. However, the elevated levels of vaccine-induced anti-PEG antibodies correlated with increased systemic reactogenicity following two doses of vaccination. We conclude that PEG-specific antibodies can be boosted by LNP mRNA-vaccination and that the rise in PEG-specific antibodies is associated with systemic reactogenicity and an increase of PEG particle–leukocyte association in human blood. The longer-term clinical impact of the increase in PEG-specific antibodies induced by lipid nanoparticle mRNA-vaccines should be monitored.
Recombinant influenza virus expressing HIV-1 p24 capsid protein induces mucosal HIV-specific CD8 T-cell responses.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.VACCINE.2016.01.030
Abstract: Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.
Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences.
Publisher: European Respiratory Society (ERS)
Date: 21-01-2021
Enhancing dendritic cell activation and HIV vaccine effectiveness through nanoparticle vaccination
Publisher: Informa UK Limited
Date: 26-02-2016
DOI: 10.1586/14760584.2016.1141054
Abstract: Novel vaccination approaches are needed to prevent and control human immunodeficiency virus (HIV) infection. A growing body of literature demonstrates the potential of nanotechnology to modulate the human immune system and generate targeted, controlled immune responses. In this Review, we summarize important advances in how 'nanovaccinology' can be used to develop safe and effective vaccines for HIV. We highlight the central role of dendritic cells in the immune response to vaccination and describe how nanotechnology can be used to enhance delivery to and activation of these important antigen-presenting cells. Strategies employed to improve biodistribution are discussed, including improved lymph node delivery and mucosal penetration concepts, before detailing methods to enhance the humoral and/or cellular immune response to vaccines. We conclude with a commentary on the current state of nanovaccinology.
The testis and epididymis are productively infected by SIV and SHIV in juvenile macaques during the post-acute stage of infection
Publisher: Springer Science and Business Media LLC
Date: 2007
Screening and development of monoclonal antibodies for identification of ferret T follicular helper cells.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2021
DOI: 10.1038/S41598-021-81389-Z
Abstract: The ferret is a key animal model for investigating the pathogenicity and transmissibility of important human viruses, and for the pre‐clinical assessment of vaccines. However, relatively little is known about the ferret immune system, due in part to a paucity of ferret‐reactive reagents. In particular, T follicular helper (Tfh) cells are critical in the generation of effective humoral responses in humans, mice and other animal models but to date it has not been possible to identify Tfh in ferrets. Here, we describe the screening and development of ferret-reactive BCL6, CXCR5 and PD-1 monoclonal antibodies. We found two commercial anti-BCL6 antibodies (clone K112-91 and clone IG191E/A8) had cross-reactivity with lymph node cells from influenza-infected ferrets. We next developed two murine monoclonal antibodies against ferret CXCR5 (clone feX5-C05) and PD-1 (clone fePD-CL1) using a single B cell PCR-based method. We were able to clearly identify Tfh cells in lymph nodes from influenza infected ferrets using these antibodies. The development of ferret Tfh marker antibodies and the identification of ferret Tfh cells will assist the evaluation of vaccine-induced Tfh responses in the ferret model and the design of novel vaccines against the infection of influenza and other viruses, including SARS-CoV2.
Modeling of antilatency treatment in HIV: What is the optimal duration of antiretroviral therapy-free HIV remission?
Publisher: American Society for Microbiology
Date: 15-12-2017
DOI: 10.1128/JVI.01395-17
Abstract: A number of treatment strategies are currently being developed to promote antiretroviral therapy-free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work, we use a stochastic model to show that a treatment that achieves a 1-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first 3 months. Given quarterly viral testing intervals, this leads to an expected 39 (95% uncertainty interval [UI], 22 to 69) heterosexual transmissions and up to 262 (95% UI, 107 to 534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the “useful” or optimal length of antiretroviral therapy-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission versus the risk of treatment failure (viral recrudescence) and the need for retreatment. To minimize drug exposure, we found that the optimal target of antilatency interventions is a 1,700-fold reduction in the size of the reservoir, which leads to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally, we show that when shorter periods are targeted, there is a real probability of viral transmission occurring between tests for viral rebound. IMPORTANCE Current treatment of HIV involves patients taking antiretroviral therapy to ensure that the level of virus remains very low or undetectable. Continuous therapy is required, as the virus persists in a latent state within cells, and when therapy is stopped, the virus rebounds, usually within 2 weeks. A major question is how to reduce the amount of persistent virus and therefore allow a delay or remission until the virus returns after ceasing therapy. In this work, we consider the probability that HIV will still rebound even after this reduction and ask what the likelihood of viral transmission would be in this case.
Modeling of Experimental Data Supports HIV Reactivation from Latency after Treatment Interruption on Average Once Every 5-8 Days.
Publisher: Public Library of Science (PLoS)
Date: 25-08-2016
Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells: Implications for HIV Vaccine Strategies
Publisher: The American Association of Immunologists
Date: 10-2007
DOI: 10.4049/JIMMUNOL.179.7.4571
Abstract: Both the magnitude and function of vaccine-induced HIV-specific CD8+ CTLs are likely to be important in the outcome of infection. We hypothesized that rapid cytolysis by CTLs may facilitate control of viral challenge. Release kinetics of the cytolytic effector molecules granzyme B and perforin, as well as the expression of the degranulation marker CD107a and IFN-γ were simultaneously studied in SIV Gag164–172 KP9-specific CD8+ T cells from Mane-A*10+ pigtail macaques. Macaques were vaccinated with either prime-boost poxvirus vector vaccines or live-attenuated SIV vaccines. Prime-boost vaccination induced Gag-specific CTLs capable of only slow (after 3 h) production of IFN-γ and with limited (& %) degranulation and granzyme B release. Vaccination with live-attenuated SIV resulted in a rapid cytolytic profile of SIV-specific CTLs with rapid (& .5 h) and robust (& % of tetramer-positive CD8+ T cells) degranulation and granzyme B release. The cytolytic phenotype following live-attenuated SIV vaccinations were similar to that associated with the partial resolution of viremia following SIVmac251 challenge of prime-boost-vaccinated macaques, albeit with less IFN-γ expression. High proportions of KP9-specific T cells expressed the costimulatory molecule CD28 when they exhibited a rapid cytolytic phenotype. The delayed cytolytic phenotype exhibited by standard vector-based vaccine-induced CTLs may limit the ability of T cell-based HIV vaccines to rapidly control acute infection following a pathogenic lentiviral exposure.
Granulocyte contamination dramatically inhibits spot formation in AIDS virus-specific ELISpot assays: Analysis and strategies to ameliorate
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.JIM.2004.12.009
Abstract: The interferon-gamma (IFNgamma) ELISpot assay has become the most critical tool for HIV vaccine evaluation. External factors affecting ELISpot results must be minimized for the data to be reliably used in vaccine research and development processes. In pre-clinical pigtail macaque studies analyzing HIV/SIV vaccine studies, we detected a strong correlation between levels of granulocytes contaminating PBMC preparations and reduction in the quality and quantity of spots in the IFNgamma ELISpot assay. Acute SHIV infection of macaques worsened granulocyte contamination of PBMC fractions and made the assay much less reliable in detecting SIV-specific T cell immunity compared to intracellular cytokine staining (ICS). This problem could be ameliorated by using an F(ab)(2) form of the MD-1 IFNgamma capture antibody, presumably reflecting that activation of granulocytes in the well by the Fc portion of the standard capture antibody disrupts spot formation. Improving the standard ELISpot assay by using an F(ab)(2) capture antibody should make it more reliable for use in critical vaccine development studies.
Aggregation by peptide conjugation rescues poor immunogenicity of the HA stem
Publisher: Public Library of Science (PLoS)
Date: 02-11-2020
Predicting the efficacy of variant-modified COVID-19 vaccine boosters
Publisher: Springer Science and Business Media LLC
Date: 03-2023
Relationship between measures of HIV reactivation and decline of the latent reservoir under latencyreversing agents
Publisher: American Society for Microbiology
Date: 05-2017
DOI: 10.1128/JVI.02092-16
Abstract: Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment. IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.
Neutralizing Antibody-Based Prevention of Cell-Associated HIV-1 Infection
Publisher: MDPI AG
Date: 18-06-2018
DOI: 10.3390/V10060333
Control of Viremia and Prevention of AIDS following Immunotherapy of SIV-Infected Macaques with Peptide-Pulsed Blood
Publisher: Public Library of Science (PLoS)
Date: 02-05-2008
Intravenous Immunoglobulin Protects Against Severe Pandemic Influenza Infection
Publisher: Elsevier BV
Date: 05-2017
Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 variants via multiplex assay
Publisher: American Society for Clinical Investigation
Date: 23-08-2021
The pigtail macaque MHC class I allele Mane-A*10 presents an immundominant SIV Gag epitope: identification, tetramer development and implications of immune escape and reversion.
Publisher: Wiley
Date: 10-08-2005
DOI: 10.1111/J.1600-0684.2005.00126.X
Abstract: Abstract: The pigtail macaque ( Macaca nemestrina ) is a common model for the study of AIDS. The pigtail major histocompatibility complex class I allele Mane‐A * 10 restricts an immunodominant simian immunodeficiency virus (SIV) Gag epitope (KP9) which rapidly mutates to escape T cell recognition following acute simian/human immunodeficiency virus infection. Two technologies for the detection of Mane‐A * 10 in outbred pigtail macaques were developed: reference strand‐mediated conformational analysis and sequence‐specific primer polymerase chain reaction. A Mane‐A*10/KP9 tetramer was then developed to quantify CD8 + T lymphocytes primed by multigenic DNA vaccination, which have previously been difficult to detect using standard interferon‐ γ ‐based T cell assays. We also demonstrate mutational escape at KP9 following acute SIV infection. Mane‐A * 10 + animals have lower set point SIV levels than Mane‐A * 10 − animals, suggesting a significant fitness cost of escape. These studies pave the way for a more robust understanding of HIV vaccines in pigtail macaques.
A systems approach to elucidate personalized mechanistic complexities of antibody-Fc receptor activation post-vaccination
Publisher: Elsevier BV
Date: 09-2021
Modulation of innate and adaptive cellular immunity relevant to HIV-1 vaccine design by seminal plasma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-01-2017
Azithromycin: More lethal than chloramphenicol?
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/SH12128
Abstract: Azithromycin is commonly used in sexual health and respiratory medicine, often when the diagnosis is presumptive. A recent article by Ray et al. reported that 1 out of 20 000 courses of low-dose azithromycin was associated with (sudden) cardiovascular death (including 1 out of 4000 courses in high-risk cardiovascular patients), ascribing these deaths to azithromycin itself. Here, we critique the actual study and examine conflicting data from randomised control trials, animal studies and observational data.
Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques
Publisher: Cold Spring Harbor Laboratory
Date: 16-12-2022
DOI: 10.1101/2022.12.14.520525
Abstract: Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naïve and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/ Mycobacterium tuberculosis (Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4-8 year-old children were intravenously infected with SIVmac239M, treated with ART three months later, and coinfected with Mtb three months after initiating ART. SIV-naïve macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naïve macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naïve macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas obtained at necropsy, nor did they differ in the frequency of immune checkpoint and proliferative markers. Thus, ART treatment of juvenile macaques, three months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naïve macaques.
Genetic vaccination strategies for enhanced cellular, humoral and mucosal immunity
Publisher: Wiley
Date: 10-1999
DOI: 10.1111/J.1600-065X.1999.TB01341.X
Abstract: In this article, we describe several novel genetic vaccination strategies designed to facilitate the development of different types of immune responses. These include: i) the consecutive use of DNA and fowlpoxvirus vectors in "prime-boost" strategies which induce greatly enhanced and sustained levels of both cell-mediated immunity and humoral immunity, including mucosal responses ii) the co-expression of genes encoding cytokines and cell-surface receptors, and the use of immunogenic carrier molecules, for immune modulation and/or improved targeting of vector-expressed vaccine antigens and iii) the expression of minimal immunogenic amino acid sequences, particularly cytotoxic CD8+ T-cell determinants, in "polytope" vector vaccines. The capacity to modulate and enhance specific immune responses by the use of approaches such as these may underpin the development of vaccines against diseases for which no effective strategies are currently available.
Host Immunity to Mycobacterium tuberculosis Infection Is Similar in Simian Immunodeficiency Virus (SIV)-Infected, Antiretroviral Therapy-Treated and SIV-Naïve Juvenile Macaques
Publisher: American Society for Microbiology
Date: 16-05-2023
DOI: 10.1128/IAI.00558-22
Abstract: Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV.
Divergent Expression of CXCR5 and CCR5 on CD4+ T Cells and the Paradoxical Accumulation of T Follicular Helper Cells during HIV Infection
Publisher: Frontiers Media SA
Date: 12-05-2017
Phenotypic and kinetic analysis of effective simian–human immunodeficiency virus-specific T cell responses in DNA- and fowlpox virus-vaccinated macaques
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.VIROL.2005.04.023
Abstract: Although T cell immunity is important in the control of HIV-1 infection, the characteristics of effective HIV-specific T cell responses are unclear. We previously observed protection from virulent SHIV challenges in macaques administered priming with DNA vaccines and boosting with recombinant fowlpox viruses expressing shared SIV Gag antigens. We therefore performed a detailed kinetic and phenotypic study of the T cell immunity induced by these vaccines prior to and following SHIV challenge utilizing intracellular cytokine staining. Pigtail macaques vaccinated intramuscularly with DNA/recombinant fowlpox virus exhibited a coordinated induction of first Gag-specific CD4 T cell responses and then a week later Gag-specific CD8 T cell responses following the fowlpox virus boost. Overall, the magnitude and timing of the peak CD8 T cell responses following challenge was significantly associated with reductions in SHIV viremia following pathogenic challenge. After pathogenic lentiviral challenge, virus-specific effector memory T cells derived from animals controlling SHIV infection recognized a broad array of epitopes, expressed multiple effector cytokines and rapidly recognized virus-exposed cells ex vivo. These results shed light on some of the requirements for T cells in the control of pathogenic lentiviral infections.
Anti-HIV-1 antibody-dependent cellular cytotoxicity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
vasive aspergillosis in AIDS
Publisher: Wiley
Date: 10-1991
DOI: 10.1111/J.1445-5994.1991.TB01383.X
Abstract: Invasive aspergillosis (IA) is a rare infection in patients with the Acquired Immune Deficiency Syndrome (AIDS). We report the first Australian cases of histologically and microbiologically proven IA diagnosed antemortem in AIDS patients. We also describe the first case of laryngeal involvement and the unusual case of a pneumothorax due to IA. These three cases illustrate the varied clinical and pathological features of IA in AIDS and highlight some of the difficulties in diagnosis and treatment. The infections occurred in the setting of advanced immunodeficiency and multiple opportunistic infections and responded poorly to treatment.
Engineering Poly(ethylene glycol) Particles for Improved Biodistribution
Publisher: American Chemical Society (ACS)
Date: 21-01-2015
DOI: 10.1021/NN5061578
Abstract: We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent). Increasing the PEG molecular weight (from 10 to 40 kDa) or decreasing the PEG particle size (from 1400 to 150 nm) reduces phagocytic blood cell association of the PEG particles. Mice biodistribution studies show that the PEG particles exhibit extended circulation times (>12 h) compared with the MS@PEG particles and that the retention of smaller PEG particles (150 nm) in blood, when compared with larger PEG particles (>400 nm), is increased at least 4-fold at 12 h after injection. Our findings highlight the influence of unique aspects of polymer hydrogel particles on biological interactions. The reported PEG hydrogel particles represent a new class of polymer carriers with potential biomedical applications.
Templated Polymer Replica Nanoparticles to Facilitate Assessment of Material-Dependent Pharmacokinetics and Biodistribution
Publisher: American Chemical Society (ACS)
Date: 25-09-2017
Abstract: Surface modification is frequently used to tailor the interactions of nanoparticles with biological systems. In many cases, the chemical nature of the treatments employed to modify the biological interface (for ex le attachment of hydrophilic polymers or targeting groups) is the focus of attention. However, isolation of the fundamental effects of the materials employed to modify the interface are often confounded by secondary effects imparted by the underlying substrate. Herein, we demonstrate that polymer replica particles templated from degradable mesoporous silica provide a facile means to evaluate the impact of surface modification on the biological interactions of nanomaterials, independent of the substrate. Poly(ethylene glycol) (PEG), poly(N-(2 hydroxypropyl)methacrylamide) (PHPMA), and poly(methacrylic acid) (PMA) were templated onto mesoporous silica and cross-linked and the residual particles were removed. The resulting nanoparticles, comprising interfacial polymer alone, were then investigated using a range of in vitro and in vivo tests. As expected, the PEG particles showed the best stealth properties, and these trends were consistent in both in vitro and in vivo studies. PMA particles showed the highest cell association in cell lines in vitro and were rapidly taken up by monocytes in ex vivo whole blood, properties consistent with the very high in vivo clearance subsequently seen in rats. In contrast, PHPMA particles showed rapid association with both granulocytes and monocytes in ex vivo whole blood, even though in vivo clearance was less rapid than the PMA particles. Rat studies confirmed better systemic exposure for PEG and PHPMA particles when compared to PMA particles. This study provides a new avenue for investigating material-dependent biological behaviors of polymer particles, irrespective of the properties of the underlying core, and provides insights for the selection of polymer particles for future biological applications.
T follicular helper cells in the humoral immune response to SARS-CoV-2 infection and vaccination
Publisher: Oxford University Press (OUP)
Date: 03-11-2022
Abstract: Vaccination remains the most effective mechanism to reduce the impact of COVID-19. Induction of neutralizing antibodies is a strong correlate of protection from infection and severe disease. An understanding of the cellular events that underpin the generation of effective neutralizing antibodies is therefore key to the development of efficacious vaccines that target emerging variants of concern. Analysis of the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and vaccination has identified circulating T follicular helper cells (cTFH) as a robust correlate of the neutralizing antibody response. Here, we discuss the analysis of cTFH cells and their lymphoid counterparts in human humoral immune responses during COVID-19, and in response to vaccination with SARS-CoV-2 spike. We discuss the phenotypic heterogeneity of cTFH cells and the utility of cTFH subsets as informative biomarkers for development of humoral immunity. We posit that the analysis of the most effective cTFH will be critical to inducing durable immunity to new variants of SARS-CoV-2.
HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells
Publisher: Frontiers Media SA
Date: 21-04-2017
Reversion of immune escape HIV variants upon transmission: insights into effective viral immunity
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.TIM.2005.03.011
Abstract: Many viruses that cause chronic viremic infections, such as human immunodeficiency virus type 1 (HIV-1), mutate extensively to avoid effective control by the host immune system. However, each immune escape mutation probably results in some fitness cost to the virus. The most effective immune responses might be those that target the regions of the virus where escape mutation inflicts the largest fitness cost to the virus. A virus crippled by immune escape mutations would result in reduced viral load and delayed disease. Such knowledge could be used to rationally design more effective vaccines.
Coformulation with tattoo ink for immunological assessment of vaccine immunogenicity in the draining lymph node
Publisher: Cold Spring Harbor Laboratory
Date: 29-08-2020
DOI: 10.1101/2020.08.27.270975
Abstract: Characterisation of germinal centre B and T cell responses yields critical insights into vaccine immunogenicity. Non-human primates are a key pre-clinical animal model for human vaccine development, allowing both lymph node and circulating immune responses to be longitudinally s led for correlates of vaccine efficacy. However, patterns of vaccine antigen drainage via the lymphatics after intramuscular immunisation can be stochastic, driving uneven deposition between lymphoid sites, and between in idual lymph nodes within larger clusters. In order to improve the accurate isolation of antigen-exposed lymph nodes during biopsies and necropsies, we developed and validated a method for co-formulating candidate vaccines with tattoo ink, which allows for direct visual identification of vaccine-draining lymph nodes and evaluation of relevant antigen-specific B and T cell responses by flow cytometry. This approach improves the assessment of vaccine-induced immunity in highly relevant non-human primate models.
Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-04-2012
Abstract: Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (T RM ) cells are identified by their expression of the α-chain from the integrin α E (CD103)β 7 , and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103 + CD8 + T RM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T RM phenotype. The CD8 + T RM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T RM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.
Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?
Publisher: Frontiers Media SA
Date: 23-01-2017
Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control
Publisher: Springer Science and Business Media LLC
Date: 04-01-2016
Systems serology detects functionally distinct coronavirus antibody features in children and elderly
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1038/S41467-021-22236-7
Abstract: The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such ergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children ( n = 89), adults ( n = 98), elderly ( n = 57), and COVID-19 patients ( n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy in iduals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy in iduals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
NKG2D Acts as a Co-Receptor for Natural Killer Cell-Mediated Anti-HIV-1 Antibody-Dependent Cellular Cytotoxicity.
Publisher: Mary Ann Liebert Inc
Date: 11-2016
Binding, internalization, and antigen presentation of vaccine-loaded nanoengineered capsules in blood
Publisher: Wiley
Date: 16-12-2008
Analysis of Pigtail Macaque Major Histocompatibility Complex Class I Molecules Presenting Immunodominant Simian Immunodeficiency Virus Epitopes
Publisher: American Society for Microbiology
Date: 15-01-2005
DOI: 10.1128/JVI.79.2.684-695.2005
Abstract: Successful human immunodeficiency virus (HIV) vaccines will need to induce effective T-cell immunity. We studied immunodominant simian immunodeficiency virus (SIV) Gag-specific T-cell responses and their restricting major histocompatibility complex (MHC) class I alleles in pigtail macaques ( Macaca nemestrina ), an increasingly common primate model for the study of HIV infection of humans. CD8 + T-cell responses to an SIV epitope, Gag 164 - 172 KP9, were present in at least 15 of 36 outbred pigtail macaques. The immunodominant KP9-specific response accounted for the majority (mean, 63%) of the SIV Gag response. Sequencing from six macaques identified 7 new Mane-A and 13 new Mane-B MHC class I alleles. One new allele, Mane-A*10 , was common to four macaques that responded to the KP9 epitope. We adapted reference strand-mediated conformational analysis (RSCA) to MHC class I genotype M. nemestrina. Mane-A*10 was detected in macaques presenting KP9 studied by RSCA but was absent from non-KP9-presenting macaques. Expressed on class I-deficient cells, Mane-A*10, but not other pigtail macaque MHC class I molecules, efficiently presented KP9 to responder T cells, confirming that Mane-A*10 restricts the KP9 epitope. Importantly, naïve pigtail macaques infected with SIV mac251 that respond to KP9 had significantly reduced plasma SIV viral levels (log 10 0.87 copies/ml P = 0.025) compared to those of macaques not responding to KP9. The identification of this common M. nemestrina MHC class I allele restricting a functionally important immunodominant SIV Gag epitope establishes a basis for studying CD8 + T-cell responses against AIDS in an important, widely available nonhuman primate species.
Specific antibody-dependent cellular cytotoxicity responses associated with slow progression of HIV infection
Publisher: Wiley
Date: 16-01-2013
DOI: 10.1111/IMM.12016
Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2022
DOI: 10.1101/2022.02.06.22270359
Abstract: Following infection with SARS-CoV-2, virus-specific antibodies are generated which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. In comparison, other antibody isotypes including IgA have been poorly characterized. Here we characterized plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. We find that convalescent plasma IgA from % of the cohort have the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated inhibition of RBD binding to ACE2 than IgG, when tested at equivalent concentrations. Plasma IgA and IgG from the cohort, broadly recognize similar RBD epitopes and showed similar ability to inhibit ACE2 from binding 22 of 23 different prevalent RBD proteins with single amino acid mutations. Plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison to plasma IgG. Overall, convalescent plasma IgA contributes to neutralisation towards wild-type RBD and various RBD single mutants in most subjects, although this response is heterogeneous and less potent than IgG.
Immune profiling of influenza‐specific B‐ and T‐cell responses in macaques using flow cytometry‐based assays
Publisher: Wiley
Date: 07-09-2020
DOI: 10.1111/IMCB.12383
Anti-Drug Antibodies in Pigtailed Macaques Receiving HIV Broadly Neutralising Antibody PGT121
Publisher: Frontiers Media SA
Date: 11-11-2021
DOI: 10.3389/FIMMU.2021.749891
Abstract: Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.
CD4+ T-cell subsets: What really counts in preventing HIV disease?
Publisher: Informa UK Limited
Date: 03-2008
Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem
Publisher: American Society for Clinical Investigation
Date: 22-01-2019
DOI: 10.1172/JCI123366
Low pH Exposure During Immunoglobulin G Purification Methods Results in Aggregates That Avidly Bind Fcγ Receptors: Implications for Measuring Fc Dependent Antibody Functions.
Publisher: Frontiers Media SA
Date: 11-10-2019
A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA
Publisher: Springer Science and Business Media LLC
Date: 10-07-2018
DOI: 10.1038/S41467-018-04704-9
Abstract: The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. Recent seasonal H3 vaccines do not protect against swine-origin H3N2 variant (H3N2v) strains that recently have caused severe human infections. Here, we report a human V H 1-69 gene-encoded monoclonal antibody (mAb) designated H3v-47 that exhibits potent cross-reactive neutralization activity against human and swine H3N2 viruses that circulated since 1989. The crystal structure and electron microscopy reconstruction of H3v-47 Fab with the H3N2v hemagglutinin (HA) identify a unique epitope spanning the vestigial esterase and receptor-binding subdomains that is distinct from that of any known neutralizing antibody for influenza A H3 viruses. MAb H3v-47 functions largely by blocking viral egress from infected cells. Interestingly, H3v-47 also engages Fcγ receptor and mediates antibody dependent cellular cytotoxicity (ADCC). This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines.
Adaptive immunity to human coronaviruses is widespread but low in magnitude
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1264
Impact of heavy rainfall events and shading on the temperature of sea turtle nests
Publisher: Springer Science and Business Media LLC
Date: 24-11-2020
Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences
Publisher: Cold Spring Harbor Laboratory
Date: 08-10-2020
DOI: 10.1101/2020.10.06.20207514
Abstract: COVID-19 causes persistent endothelial inflammation, lung and cardiovascular complications. SARS-CoV-2 utilises the catalytic site of full-length membrane-bound angiotensin converting enzyme 2 (ACE2) for cell entry causing downregulation of tissue ACE2. We reported downregulation of cardiac ACE2 is associated with increased plasma ACE2 activity. In this prospective observational study in recovered COVID-19 patients, we hypothesised that SARS-CoV-2 infection would be associated with shedding of ACE2 from cell membranes and increased plasma ACE2 activity. We measured plasma ACE2 catalytic activity using a validated, sensitive quenched fluorescent substrate-based assay in a cohort of Australians aged ≥18 years (n=66) who had recovered from mild, moderate or severe SARS-CoV-2 infection (positive result by PCR testing) and age and gender matched uninfected controls (n=70). Serial s les were available in 23 recovered SARS-CoV-2 patients. Plasma ACE2 activity at a median of 35 days post-infection [interquartile range 30-38 days] was 97-fold higher in recovered SARS-CoV-2 patients compared to controls (5.8 [2-11.3] vs. 0.06 [0.02-2.2] pmol/min/ml, p .0001). There was a significant difference in plasma ACE2 activity according to disease severity (p=0.033), with severe COVID-19 associated with higher ACE2 activity compared to mild disease (p=0.027). Men (n=39) who were SARS-CoV-2 positive had higher median plasma ACE2 levels compared to women (n=27) (p .0001). We next analysed whether an elevated plasma ACE2 activity level persisted following SARS-CoV-2 infection in subjects with blood s les at 63 [56-65] and 114 [111-125] days post infection. Plasma ACE2 activity remained persistently elevated in almost all subjects, with no significant differences between timepoints in post-hoc comparisons (p .05). This is the first description that plasma ACE2 activity is elevated after COVID-19 infection, and the first with longitudinal data indicating plasma ACE2 activity remains elevated out to a median of 114 days post-infection. Larger studies are now needed to determine if persistent elevated plasma ACE2 activity identifies people at risk of prolonged illness following COVID-19.
Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19
Publisher: Springer Science and Business Media LLC
Date: 13-07-2020
Impact of alemtuzumab on HIV persistence in an HIV-infected individual on antiretroviral therapy with Sezary syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2017
Influenza Virus Infection Enhances Antibody-Mediated NK Cell Functions via Type I Interferon-Dependent Pathways
Publisher: American Society for Microbiology
Date: 03-2019
DOI: 10.1128/JVI.02090-18
Abstract: Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza virus infection. We found that type I interferon released in response to influenza virus infection primes NK cells to become highly reactive to anti-influenza virus ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.
Neutrophils mediate HIV-specific antibody-dependent phagocytosis and ADCC
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JIM.2018.03.007
Abstract: There is growing evidence to support the role of Fc-mediated effector functions, such as Antibody-Dependent Cellular cytotoxicity (ADCC) and Antibody-Dependent Phagocytosis (ADP) in the protection and control of HIV. The RV144 trial and other recent HIV vaccine studies have highlighted the importance of ADCC responses in protection against HIV. The role of neutrophils, the most abundant leukocyte in the blood, has not been thoroughly evaluated for Fc-mediated effector functions to HIV. We optimized HIV-specific neutrophil ADCC and Antibody-Dependent Neutrophil Phagocytosis (ADNP) assays using freshly isolated primary human neutrophils from blood. We also developed methods to study ADP using the neutrophil-like HL-60 cell line. We found that neutrophils mediate both HIV-specific ADP and ADCC responses. In vitro, neutrophil-mediated ADCC responses peaked at 4 h, much faster than primary NK cell or monocyte-mediated responses. We detected a wide range of responses in the ADNP, HL-60 mediated ADP and ADCC across a cohort of 41 viremic antiretroviral therapy naïve HIV positive subjects. HL-60 and Neutrophil-mediated ADP and ADCC responses correlated well with each other, suggesting that they measure overlapping functions. The ADNP and HL-60 ADP inversely correlated with HIV viral load, suggesting that these antibody-mediated neutrophil-based assays should prove useful in dissecting HIV-specific immunity.
HIV Vaccine efficacy trial: Glimmers of hope and the potential role of antibody-dependent cellular cytotoxicity
Publisher: Informa UK Limited
Date: 04-2011
DOI: 10.4161/HV.7.4.14123
Abstract: The partial efficacy of the recent HIV-1 vaccine trial in Thailand has rejuvenated the HIV vaccine field. There are now clear opportunities to dissect the potential correlates of protection against HIV-1. Comparisons of three major HIV-1 vaccine strategies used in human efficacy trials to date highlight a possible role for antibody-dependent cellular cytotoxicty (ADCC), rather than cytotoxic T lymphocyte or neutralizing antibody responses, in protective immunity. This review explores the HIV vaccine efficacy trials performed to date and the potential role for ADCC antibodies in assisting protective immunity.
High Levels of Human Antigen-Specific CD4(+) T Cells in Peripheral Blood Revealed by Stimulated Coexpression of CD25 and CD134 (OX40)
Publisher: The American Association of Immunologists
Date: 15-08-2009
Abstract: Ag-specific human CD4+ memory T lymphocytes have mostly been studied using assays of proliferation in vitro. Intracellular cytokine and ELISPOT assays quantify effector cell populations but barely detect responses to certain recall Ags that elicit strong proliferative responses, e.g., tetanus toxoid, that comprise non-Th1 CD4+ cells. We have found that culturing whole blood with Ag for 40–48 h induces specific CD4+ T cells to simultaneously express CD25 and CD134. This new technique readily detects responses to well-described CD4+ T cell recall Ags, including preparations of mycobacteria, CMV, HSV-1, influenza, tetanus toxoid, Candida albicans, and streptokinase, as well as HIV-1 peptides, with high specificity. The assay detects much higher levels of Ag-specific cells than intracellular cytokine assays, plus the cells retain viability and can be sorted for in vitro expansion. Furthermore, current in vitro assays for human CD4+ memory T lymphocytes are too labor-intensive and difficult to standardize for routine diagnostic laboratories, whereas the whole-blood CD25+CD134+ assay combines simplicity of setup with a straightforward cell surface flow cytometry readout. In addition to revealing the true extent of Ag-specific human CD4+ memory T lymphocytes, its greatest use will be as a simple in vitro monitor of CD4+ T cell responses to Ags such as tuberculosis infection or vaccines.
Cellular Interactions of Liposomes and PISA Nanoparticles during Human Blood Flow in a Microvascular Network
Publisher: Wiley
Date: 25-06-2020
Peripheral NKT Cells in Simian Immunodeficiency Virus-Infected Macaques
Publisher: American Society for Microbiology
Date: 15-02-2009
DOI: 10.1128/JVI.02138-08
Abstract: NKT cells are a specialized population of T lymphocytes that have an increasingly recognized role in immunoregulation, including controlling the response to viral infections. The characteristics of NKT cells in the peripheral blood of macaques during simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (HIV) (SHIV) infection were assessed. NKT cells comprised a mean of 0.19% of peripheral blood lymphocytes across the 64 uninfected macaques studied. Although the range in the percentages of NKT cells was large (0 to 2.2%), levels were stable over time within in idual macaques without SIV/SHIV infection. The majority of NKT cells in macaques were CD4 + (on average 67%) with smaller populations being CD8 + (21%) and CD4/CD8 double positive (13%). A precipitous decline in CD4 + NKT cells occurred in all six macaques infected with CXCR4-tropic SHIV mn229 early after infection, with a concomitant rise in CD8 + NKT cells in some animals. The depletion of CD4 + NKT cells was tightly correlated with the depletion of total CD4 + T cells. R5-tropic SIV mac251 infection of macaques resulted in a slower and more variable decline in CD4 + NKT cells, with animals that were able to control SIV virus levels maintaining higher levels of CD4 + NKT cells. An inverse correlation between the depletion of total and CD4 + NKT cells and SIV viral load during chronic infection was observed. Our results demonstrate the infection-driven depletion of peripheral CD4 + NKT cells during both SHIV and SIV infection of macaques. Further studies of the implications of the loss of NKT cell subsets in the pathogenesis of HIV disease are needed.
Understanding the treatment benefit of hyperimmune anti-influenza intravenous immunoglobulin (Flu-IVIG) for severe human influenza
Publisher: American Society for Clinical Investigation
Date: 24-07-2023
Ageing in patients with chronic HIV infection: impact of hypercoagulation
Publisher: Springer Science and Business Media LLC
Date: 24-11-2018
Monoclonal antibody levels and protection from COVID-19
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2022
DOI: 10.1101/2022.11.22.22282199
Abstract: Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies in preventing symptomatic SARS-CoV-2 infection. We use data on changes in the in vivo concentration of monoclonal antibodies, and the associated protection from COVID-19, over time to model the dose-response relationship of monoclonal antibodies for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a monoclonal antibody concentration of 54-fold of the in vitro IC50 (95% CI: 16 – 183). This relationship provides a quantitative tool allowing prediction of the prophylactic efficacy and duration of protection for new monoclonal antibodies administered at different doses and against different SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either monoclonal antibody treatment or vaccination. We find no evidence for a difference between the 50% protective titer for monoclonal antibodies and vaccination.
Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis
Publisher: Elsevier BV
Date: 2022
The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens
Publisher: Wiley
Date: 03-02-2020
DOI: 10.1111/IMCB.12312
Abstract: In recent years, there has been a renewed interest in utilizing antibody fragment crystallizable (Fc) functions to prevent and control viral infections. The protective and therapeutic potential of Fc-mediated antibody functions have been assessed for some clinically important human viruses, including HIV, hemorrhagic fever viruses and influenza virus. There is mounting evidence that influenza-specific antibodies with Fc-mediated functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis, can aid in the clearance of influenza virus infection. Recent influenza challenge studies and intravenous immunoglobulin G therapy studies in humans suggest a protective role for Fc effector functions in vivo. Broadly reactive influenza antibodies with Fc-mediated functions are prevalent in the human population and could inform the development of a universally protective influenza vaccine or therapy. In this review, we explore the utility of antibodies with Fc-mediated effector functions against viral infections with a focus on influenza virus.
Timing of Immune Escape Linked to Success or Failure of Vaccination
Publisher: Public Library of Science (PLoS)
Date: 16-09-2010
Interactions of core cross-linked poly(2-oxazoline) and poly(2-oxazine) micelles with immune cells in human blood
Publisher: Elsevier BV
Date: 07-2021
Template-Mediated Assembly of DNA into Microcapsules for Immunological Modulation
Publisher: Wiley
Date: 06-08-2020
An Inflammatory Story: Antibodies in Tuberculosis Comorbidities
Publisher: Frontiers Media SA
Date: 09-12-2019
Plasma Corona Protects Human Immune Cells from Structurally Nanoengineered Antimicrobial Peptide Polymers
Publisher: American Chemical Society (ACS)
Date: 13-07-2021
P09-07. Balancing reversion of CTL and neutralizing antibody escape mutations within HIV-1 Env upon transmission
Publisher: Springer Science and Business Media LLC
Date: 10-2009
P09-08. The complexity of the infecting inoculum determines the outcome of infection
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Paradox of Protection: Preferential Recognition of CD4-induced Epitopes by Anti-HIV-1 ADCC Antibodies
Publisher: Elsevier BV
Date: 10-2015
Rapid recall andde novoT cell responses during SARS-CoV-2 breakthrough infection
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2022
DOI: 10.1101/2022.12.19.521129
Abstract: While the protective role of neutralising antibodies against COVID-19 is well-established, questions remain about the relative importance of cellular immunity. Using 6 pMHC-multimers in a cohort with early and frequent s ling we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection. Recall of spike-specific CD4 + T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post-symptom onset. Similarly, spike-specific CD8 + T cells were rapidly activated but showed variable levels of expansion. Strikingly, high levels of SARS-CoV-2-specific CD8 + T cell activation at baseline and peak were strongly correlated with reduced peak SARS-CoV-2 RNA levels in nasal swabs and accelerated clearance of virus. Our study demonstrates rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8 + T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.
Replication-Competent Simian Immunodeficiency Virus (SIV) Gag Escape Mutations Archived in Latent Reservoirs during Antiretroviral Treatment of SIV-Infected Macaques
Publisher: American Society for Microbiology
Date: 09-2011
DOI: 10.1128/JVI.00366-11
Abstract: In response to pressure exerted by major histocompatibility complex (MHC) class I-mediated CD8 + T cell control, human immunodeficiency virus (HIV) escape mutations often arise in immunodominant epitopes recognized by MHC class I alleles. While the current standard of care for HIV-infected patients is treatment with highly active antiretroviral therapy (HAART), suppression of viral replication in these patients is not absolute and latently infected cells persist as lifelong reservoirs. To determine whether HIV escape from MHC class I-restricted CD8 + T cell control develops during HAART treatment and then enters latent reservoirs in the periphery and central nervous system (CNS), with the potential to emerge as replication-competent virus, we tracked the longitudinal development of the simian immunodeficiency virus (SIV) Gag escape mutation K165R in HAART-treated SIV-infected pigtailed macaques. Key findings of these studies included: (i) SIV Gag K165R escape mutations emerged in both plasma and cerebrospinal fluid (CSF) during the decaying phase of viremia after HAART initiation before suppression of viral replication, (ii) SIV K165R Gag escape mutations were archived in latent proviral DNA reservoirs, including the brain in animals receiving HAART that suppressed viral replication, and (iii) replication-competent SIV Gag K165R escape mutations were present in the resting CD4 + T cell reservoir in HAART-treated SIV-infected macaques. Despite early administration of aggressive antiretroviral treatment, HIV immune escape from CD8 + T cell control can still develop during the decaying phases of viremia and then persist in latent reservoirs, including the brain, with the potential to emerge if HAART therapy is interrupted.
Reduced hepatitis B virus (HBV)-specific CD4+T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy
Publisher: American Society for Microbiology
Date: 03-2005
DOI: 10.1128/JVI.79.5.3038-3051.2005
Abstract: Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in in iduals chronically infected with HBV compared to in iduals with self-limiting HBV infection or those on anti-HBV therapy. In in iduals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with erse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4 + and CD8 + T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers ( n = 34) were studied, including in iduals never treated for HBV infection ( n = 7), HBV-infected in iduals receiving anti-HBV therapy ( n = 13), and HIV-1-HBV-coinfected in iduals receiving anti-HBV therapy ( n = 14). CD4 + and CD8 + HBV-specific T-cell responses were more frequently detected and the CD8 + T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4 + and CD8 + T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8 + T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4 + T-cell responses were significantly reduced in HIV-1-HBV-coinfected in iduals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.
Influenza-specific antibody-dependent phagocytosis
Publisher: Public Library of Science (PLoS)
Date: 28-04-2016
A Phase 1 Human Immunodeficiency Virus Vaccine Trial for Cross-Profiling the Kinetics of Serum and Mucosal Antibody Responses to CN54gp140 Modulated by Two Homologous Prime-Boost Vaccine Regimens
Publisher: Frontiers Media SA
Date: 24-05-2017
Corrigendum: Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination
Publisher: Frontiers Media SA
Date: 27-02-2018
Induction of HIV-1 subtype B and AE-specific neutralizing antibodies in mice and macaques with DNA prime and recombinant gp140 protein boost regimens.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.VACCINE.2009.08.016
Abstract: We developed highly expressing clade B and AE DNA and envelope protein (Env) vaccines for evaluation in mice and macaques as DNA prime rotein boost regimens. High levels of Env-specific antibodies were induced in mice, albeit with limited neutralizing activity in vitro. A combined clade B and AE regimen induced high titer Env-specific antibody in two pigtail macaques that neutralized several strains of HIV-1. However, upon mucosal challenge with SHIV(SF162P3) no protection from infection was observed. Although the vaccines tested provide a platform for inducing robust humoral immunity, further refinements to broaden coverage against ergent strains and induce mucosal immunity are needed.
High Precursor Frequency and Promiscuity in Αβ T Cell Receptor Pairing Underpin CD8+ T-Cell Responses to an Immunodominant SARS-CoV-2 Nucleocapsid Epitope
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3751796
Fc functional antibody responses to adjuvanted versus unadjuvanted seasonal influenza vaccination in community-dwelling older adults
Publisher: Elsevier BV
Date: 02-2020
Polymorphisms and interspecies differences of the activating and inhibitory FcγRII of Macaca nemestrina influence the binding of human IgG subclasses.
Publisher: The American Association of Immunologists
Date: 15-01-2014
Abstract: Little is known of the impact of Fc receptor (FcR) polymorphism in macaques on the binding of human (hu)IgG, and nothing is known of this interaction in the pig-tailed macaque (Macaca nemestrina), which is used in preclinical evaluation of vaccines and therapeutic Abs. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcγRIIa (mnFcγRIIa) and inhibitory FcγRIIb (mnFcγRIIb) and predicted their structures using the huIgGFc/huFcγRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcγRIIa and mnFcγRIIb compared with their human FcR counterparts. MnFcγRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFcγRIIa (His131). In contrast, mnFcγRIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFcγRIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFcγRIIa showed that Pro159 and Tyr160 impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcγRIIb was shown to be dependent on His131 and Met132. Significantly, both His131 and Met132 are conserved across FcγRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcγRIIa wherein proline at position 131, also an important polymorphic site in huFcγRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFcγRIIa His131. These marked interspecies differences in IgG binding between human and macaque FcRs and polymorphisms within species have implications for preclinical evaluation of Abs and vaccines in macaques.
Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation
Publisher: Research Square Platform LLC
Date: 04-10-2021
DOI: 10.21203/RS.3.RS-745648/V1
Abstract: Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4 + and CD8 + T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.
Evaluation of Recombinant Influenza Virus-Simian Immunodeficiency Virus Vaccines in Macaques
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/JVI.00470-09
Abstract: There is an urgent need for human immunodeficiency virus (HIV) vaccines that induce robust mucosal immunity. Influenza A viruses (both H1N1 and H3N2) were engineered to express simian immunodeficiency virus (SIV) CD8 T-cell epitopes and evaluated following administration to the respiratory tracts of 11 pigtail macaques. Influenza virus was readily detected from respiratory tract secretions, although the infections were asymptomatic. Animals seroconverted to influenza virus and generated CD8 and CD4 T-cell responses to influenza virus proteins. SIV-specific CD8 T-cell responses bearing the mucosal homing marker β7 integrin were induced by vaccination of naïve animals. Further, SIV-specific CD8 T-cell responses could be boosted by recombinant influenza virus-SIV vaccination of animals with already-established SIV infection. Sequential vaccination with influenza virus-SIV recombinants of different subtypes (H1N1 followed by H3N2 or vice versa) produced only a limited boost in immunity, probably reflecting T-cell immunity to conserved internal proteins of influenza A virus. SIV challenge of macaques vaccinated with an influenza virus expressing a single SIV CD8 T cell resulted in a large anamnestic recall CD8 T-cell response, but immune escape rapidly ensued and there was no impact on chronic SIV viremia. Although our results suggest that influenza virus-HIV vaccines hold promise for the induction of mucosal immunity to HIV, broader antigen cover will be needed to limit cytotoxic T-lymphocyte escape.
Short Communication: Effect of Seminal Plasma on Functions of Monocytes and Granulocytes
Publisher: Mary Ann Liebert Inc
Date: 06-2019
Evidence of Recombination between 3′ and 5′ LTRs in Macaques Inoculated with SIV DNA
Publisher: Mary Ann Liebert Inc
Date: 10-02-2002
DOI: 10.1089/08892220252781293
Abstract: Proviral SIV DNA inoculation of macaques is an efficient method to initiate wild-type and attenuated SIV infections. However, we found that macaques inoculated with SIV DNA engineered to contain a single 105-bp deletion in the 3' nef/LTR overlap region had SIV sequences subsequently isolated that had partially or fully repaired the deletion with wild-type sequence. Animals inoculated with SIV DNA containing identical deletions in both the 5' and 3' LTRs did not repair the deletion. Recombination events occurred early, most likely by homologous recombination with sequences from the wild-type 5' LTR. This sequence analysis is the first demonstration of homologous recombination in vivo following administration of a single SIV strain.
Charge Has a Marked Influence on Hyperbranched Polymer Nanoparticle Association in Whole Human Blood
Publisher: American Chemical Society (ACS)
Date: 17-05-2017
Mucosal IL-4R antagonist HIV vaccination with SOSIP-gp140 booster can induce high-quality cytotoxic CD4+/CD8+ T cells and humoral responses in macaques
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
DOI: 10.1038/S41598-020-79172-7
Abstract: Inducing humoral, cellular and mucosal immunity is likely to improve the effectiveness of HIV-1 vaccine strategies. Here, we tested a vaccine regimen in pigtail macaques using an intranasal (i.n.) recombinant Fowl Pox Virus (FPV)- gag pol env -IL-4R antagonist prime, intramuscular (i.m.) recombinant Modified Vaccinia Ankara Virus (MVA)- gag pol -IL-4R antagonist boost followed by an i.m SOSIP-gp140 boost. The viral vector—expressed IL-4R antagonist transiently inhibited IL-4/IL-13 signalling at the vaccination site. The SOSIP booster not only induced gp140-specific IgG, ADCC (antibody-dependent cellular cytotoxicity) and some neutralisation activity, but also bolstered the HIV-specific cellular and humoral responses. Specifically, superior sustained systemic and mucosal HIV Gag-specific poly-functional/cytotoxic CD4 + and CD8 + T cells were detected with the IL-4R antagonist adjuvanted strategy compared to the unadjuvanted control. In the systemic compartment elevated Granzyme K expression was linked to CD4 + T cells, whilst Granzyme B/TIA-1 to CD8 + T cells. In contrast, the cytotoxic marker expression by mucosal CD4 + and CD8 + T cells differed according to the mucosal compartment. This vector-based mucosal IL-4R antagonist/SOSIP booster strategy, which promotes cytotoxic mucosal CD4 + T cells at the first line of defence, and cytotoxic CD4 + and CD8 + T cells plus functional antibodies in the blood, may prove valuable in combating mucosal infection with HIV-1 and warrants further investigation.
Loss of Control of HIV Viremia Associated with the Fat Malabsorption Drug Orlistat
Publisher: Mary Ann Liebert Inc
Date: 09-2012
Establishment and recall of SARS-CoV-2 spike epitope-specific CD4+ T cell memory
Publisher: Springer Science and Business Media LLC
Date: 21-03-2022
DOI: 10.1038/S41590-022-01175-5
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4
Altered affinity to ACE2 and reduced Fc functional antibodies to SARS-CoV-2 RBD variants
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2022
DOI: 10.1101/2022.07.07.22277364
Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains a formidable challenge to worldwide public health. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. We comprehensively investigated the impact of RBD mutations, including 6 variants of concern (VOC) or interest (Alpha, Beta, Gamma, Delta, Kappa and Omicron) and 33 common point mutations, on IgG recognition, FcγR-engagement, and ACE2-binding inhibition in plasma from BNT162b2-vaccine recipients (two-weeks following second dose) and mild-to-moderate COVID-19 convalescent subjects using our custom bead-based 39-plex array. We observed that IgG-recognition and FcγR-binding antibodies were most profoundly decreased against Beta and Omicron RBDs, as well as point mutations G446S, found in Omicron, and N501T, a key mutation found in animal adapted SARS-CoV-2 viruses. Measurement of RBD-ACE2 binding affinity via Biolayer Interferometry showed all VOC RBDs have enhanced affinity to human ACE2. Furthermore we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695), K26R (rs4646116) and S19P (rs73635825), have altered binding kinetics to the RBD of VOCs potentially affecting virus-host interaction and thereby host susceptibility.
Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine
Publisher: Elsevier BV
Date: 06-2022
Prime-boost protein subunit vaccines against SARSCoV-2 are highly immunogenic in mice and macaques
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2020
DOI: 10.1101/2020.09.01.278630
Abstract: SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assessed prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD was associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augmented neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines were comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.
Coformulation with tattoo ink for immunological assessment of vaccine immunogenicity in the draining lymph node
Publisher: The American Association of Immunologists
Date: 15-07-2021
Abstract: Characterization of germinal center B and T cell responses yields critical insights into vaccine immunogenicity. Nonhuman primates are a key preclinical animal model for human vaccine development, allowing both lymph node (LN) and circulating immune responses to be longitudinally s led for correlates of vaccine efficacy. However, patterns of vaccine Ag drainage via the lymphatics after i.m. immunization can be stochastic, driving uneven deposition between lymphoid sites and between in idual LN within larger clusters. To improve the accurate isolation of Ag-exposed LN during biopsies and necropsies, we developed and validated a method for coformulating candidate vaccines with tattoo ink in both mice and pigtail macaques. This method allowed for direct visual identification of vaccine-draining LN and evaluation of relevant Ag-specific B and T cell responses by flow cytometry. This approach is a significant advancement in improving the assessment of vaccine-induced immunity in highly relevant nonhuman primate models.
Age-Associated Cross-reactive Antibody-Dependent Cellular Cytotoxicity Toward 2009 Pandemic Influenza A Virus Subtype H1N1
Publisher: Oxford University Press (OUP)
Date: 28-06-2013
Abstract: During the 2009 pandemic of influenza A virus subtype H1N1 (A[H1N1]pdm09) infection, older in iduals were partially protected from severe disease. It is not known whether preexisting antibodies with effector functions such as antibody-dependent cellular cytotoxicity (ADCC) contributed to the immunity observed. We tested serum specimens obtained from 182 in iduals aged 1-72 years that were collected either immediately before or after the A(H1N1)pdm09 pandemic for ADCC antibodies to the A(H1N1)pdm09 hemagglutinin (HA) protein. A(H1N1)pdm09 HA-specific ADCC antibodies were detected in almost all in iduals aged >45 years (28/31 subjects) before the 2009 A(H1N1) pandemic. Conversely, only approximately half of the in iduals aged 1-14 years (11/31) and 15-45 years (17/31) had cross-reactive ADCC antibodies before the 2009 A(H1N1) pandemic. The A(H1N1)pdm09-specific ADCC antibodies were able to efficiently mediate the killing of influenza virus-infected respiratory epithelial cells. Further, subjects >45 years of age had higher ADCC titers to a range of seasonal H1N1 HA proteins, including from the 1918 virus, compared with younger in iduals. ADCC antibodies may have contributed to the protection exhibited in older in iduals during the 2009 A(H1N1) pandemic. This work has significant implications for improved vaccination strategies for future influenza pandemics.
A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination
Publisher: Frontiers Media SA
Date: 22-02-2022
DOI: 10.3389/FIMMU.2022.820148
Abstract: Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. In iduals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.
Mucosal antibody responses following Vaxzevria vaccination.
Publisher: Wiley
Date: 05-09-2023
DOI: 10.1111/IMCB.12685
Predicting vaccine effectiveness against severe COVID-19 over time and against variants: a meta-analysis
Publisher: Springer Science and Business Media LLC
Date: 24-03-2023
DOI: 10.1038/S41467-023-37176-7
Abstract: Vaccine protection from symptomatic SARS-CoV-2 infection has been shown to be strongly correlated with neutralising antibody titres however, this has not yet been demonstrated for severe COVID-19. To explore whether this relationship also holds for severe COVID-19, we performed a systematic search for studies reporting on protection against different SARS-CoV-2 clinical endpoints and extracted data from 15 studies. Since matched neutralising antibody titres were not available, we used the vaccine regimen, time since vaccination and variant of concern to predict corresponding neutralising antibody titres. We then compared the observed vaccine effectiveness reported in these studies to the protection predicted by a previously published model of the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. We find that predicted neutralising antibody titres are strongly correlated with observed vaccine effectiveness against symptomatic (Spearman $$\\rho$$ ρ = 0.95, p 0.001) and severe (Spearman $$\\rho$$ ρ = 0.72, p 0.001 for both) COVID-19 and that the loss of neutralising antibodies over time and to new variants are strongly predictive of observed vaccine protection against severe COVID-19.
Tentative first steps to eradicate latent HIV
Publisher: Elsevier BV
Date: 10-2014
Butyrophilin 2A1 is essential for phosphoantigen reactivity by gd T cells
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-02-2020
Abstract: In contrast to the well-studied αβ T cells, which recognize peptide antigens presented by major histocompatibility complex (MHC) and MHC-like molecules, how γδ T cells recognize antigens remains largely a mystery. One major class of γδ T cells, designated Vγ9Vδ2 + , is activated by small, phosphorylated nonpeptide antigens, or phosphoantigens, produced by microbes and cancer cells. Rigau et al. found that these cells needed the combination of two immunoglobulin superfamily members, butyrophilin 2A1 (BTN2A1) and BTN3A1, on their cell surface to recognize these phosphoantigens. BTN2A1 directly binds the Vγ9 + domain of the T cell receptor (TCR), whereas a second ligand, potentially BTN3A1, binds the Vδ2 and γ-chain regions on the opposite side of the TCR. A better understanding of this unexpected form of T cell antigen recognition should inform and enhance future γδ T cell–mediated immunotherapies. Science , this issue p. eaay5516
Influence of Cytokines on HIV-Specific Antibody-Dependent Cellular Cytotoxicity Activation Profile of Natural Killer Cells
Publisher: Public Library of Science (PLoS)
Date: 11-06-2012
Lymphoproliferative immune function in the Sydney Blood Bank Cohort, infected with natural nef/long terminal repeat mutants, and in other long-term survivors of transfusion-acquired HIV-1 infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1997
DOI: 10.1097/00002030-199713000-00004
Abstract: To assess T-helper cell immune function (proliferation) in members of the Sydney Blood Bank Cohort (SBBC) compared with other in iduals with transfusion- and sexually acquired HIV-1 infection and with matched HIV-negative controls. Decreasing CD4 counts and T-helper cell function are associated with disease progression. Peripheral blood mononuclear cells (PBMC) from study subjects were assayed for in vitro proliferative responses to HIV-1-derived antigens, recall antigens and alloantigen. T-helper cell function and CD4 counts in members of the SBBC were followed longitudinally. Proliferative responses and CD4 counts from members of the SBBC were similar to or better than those of other transfusion- or sexually-acquired HIV-1-positive long-term non-progressors (LTNP), including the HIV-negative matched SBBC control groups. However, in iduals with disease progression had reduced or undetectable proliferative responses to recall antigens but a conserved response to alloantigen they also had low CD4 counts and low CD4:CD8 ratios. In the SBBC, these immune parameters were usually stable over time. The unique SBBC with natural nef/long terminal repeat deletions in the HIV-1 genome were genuine LTNP without showing signs of disease progression. They appeared to be a group distinct from the tail-end of the normal distribution of disease progression rates, and may remain asymptomatic indefinitely. The SBBC virus may form the basis of a live attenuated immunotherapeutic or immunoprophylactic HIV vaccine.
Limited Maintenance of Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 T-Cell Receptor Clonotypes after Virus Challenge
Publisher: American Society for Microbiology
Date: 08-2008
DOI: 10.1128/JVI.00607-08
Abstract: T-cell receptors (TCRs) govern the specificity, efficacy, and cross-reactivity of CD8 T cells. Here, we studied CD8 T-cell clonotypes from Mane-A*10 + pigtail macaques responding to the simian immunodeficiency virus (SIV) Gag KP9 epitope in a setting of vaccination and subsequent viral challenge. We observed a erse TCR repertoire after DNA, recombinant poxvirus, and live attenuated virus vaccination, with none of 59 vaccine-induced KP9-specific TCRs being identical between macaques. The KP9-specific TCR repertoires remained erse after SIV or simian-human immunodeficiency virus challenge but, remarkably, exhibited substantially different clonotypic compositions compared to the corresponding populations prechallenge. Within serial s les from in idual pigtail macaques, only a small subset (33.9%) of TCRs induced by vaccination were maintained or expanded after challenge. Most (66.1%) of the TCRs induced by vaccination were not detectable after challenge. Our results suggest that some CD8 T cells induced by vaccination are more efficient than others at responding to a viral challenge. These findings have implications for future AIDS virus vaccine studies, which should consider the “fitness” of vaccine-induced T cells in order to generate robust responses in the face of virus exposure.
Safety, immunogenicity and efficacy of peptide‐pulsed cellular immunotherapy in macaques
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1600-0684.2008.00329.X
Abstract: Simple and effective delivery methods for cellular immunotherapies are needed. We recently published on the effectiveness of using ex vivo pulsing of overlapping SIV Gag 15mer peptides onto fresh peripheral blood cells in 32 SIV(mac251)-infected pigtail macaques. We now report on the safety of this approach, analysis of a novel assay for immunogenicity, the effect of an MHC allele, Mane-A*10, on CD8 T cell escape occurring and disease outcome. The vaccine strategy was safe, with no perturbations in weight or hematological profiles in comparison to controls. The high levels of SIV-specific T cell immunogenicity of this approach was confirmed using a novel assay measuring upregulation of surface CD134 of CD4 T cells. A substantial effect of the Mane-A*10 allele in reducing SIV viral load of pigtail macaques was observed in both vaccinees and controls the virologic efficacy of the immunotherapy in comparison to controls was greatest in Mane-A*10- animals. Escape mutations at several new CD8 T cell epitopes throughout the SIV proteome were observed, primarily in animals with poorer virologic control. In summary, we provide further information that peptide-pulsed PBMC are a safe, immunogenic and effective immunotherapy. The observed influence of MHC alleles and immune escape allows us to design more insightful future immunotherapy studies.
P19-24. Evaluation of recombinant influenza-SIV vaccines in macaques
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Broad spectrum SARS-CoV-2-specific immunity in hospitalized First Nations peoples recovering from COVID-19
Publisher: Wiley
Date: 19-09-2023
DOI: 10.1111/IMCB.12691
Predicting the efficacy of variant-modified COVID-19 vaccine boosters
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2022
DOI: 10.1101/2022.08.25.22279237
Abstract: As a result of the emergence and circulation of antigenically distinct SARS-CoV-2 variants, a number of variant-modified COVID-19 vaccines have been developed. Here we perform a meta-analysis of the available data on neutralisation titres from clinical studies comparing booster vaccination with either the current ancestral-based vaccines or variant-modified vaccines. We then use this to predict the relative efficacies of these booster vaccines under different scenarios.
Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques.
Publisher: American Society for Microbiology
Date: 04-2013
DOI: 10.1128/JVI.02497-12
Abstract: T follicular helper (Tfh) cells are a specialized subset of memory CD4 + T cells that are found exclusively within the germinal centers of secondary lymphoid tissues and are important for adaptive antibody responses and B cell memory. Tfh cells do not express CCR5, the primary entry coreceptor for both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), and therefore, we hypothesized that these cells would avoid infection. We studied lymph nodes and spleens from pigtail macaques infected with pathogenic strain SIVmac239 or SIVmac251, to investigate the susceptibility of Tfh cells to SIV infection. Pigtail macaque PD-1 high CD127 low memory CD4 + T cells have a phenotype comparable to that of human Tfh cells, expressing high levels of CXCR5, interleukin-21 (IL-21), Bcl-6, and inducible T cell costimulator (ICOS). As judged by either proviral DNA or cell-associated viral RNA measurements, macaque Tfh cells were infected with SIV at levels comparable to those in other CD4 + memory T cells. Infection of macaque Tfh cells was evident within weeks of inoculation, yet we confirmed that Tfh cells do not express CCR5 or either of the well-known alternative SIV coreceptors, CXCR6 and GPR15. Mutations in the SIV envelope gp120 region occurred in chronically infected macaques but were uniform across each T cell subset investigated, indicating that the viruses used the same coreceptors to enter different cell subsets. Early infection of Tfh cells represents an unexpected focus of viral infection. Infection of Tfh cells does not interrupt antibody production but may be a factor that limits the quality of antibody responses and has implications for assessing the size of the viral reservoir.
Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine
Publisher: American Chemical Society (ACS)
Date: 27-06-2022
Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (Macaca nemestrina) model
Publisher: Mary Ann Liebert Inc
Date: 06-2006
Abstract: The global impact of HIV/AIDS intensifies the need for a preventive vaccine and nonhuman primate models can help provide critical insights into effective immunity. Pigtail macaques (Macaca nemestrina) are increasingly studied as a nonhuman primate model for AIDS. We compared the virologic and immunologic characteristics of HIV-1, SIV, and SHIV infection of naive pigtail macaques across a series of preclinical HIV vaccine studies. SIVmac251 and SIVmac239 infection of naive pigtail macaques resulted in a gradual decline in peripheral CD4+ T cells in the setting of high levels of viremia, approximating most closely human infection of HIV-1. In contrast, the CXCR4-utilizing SHIVmn229 virus resulted in rapid depletion of CD4+ T cells and minimal generation of humoral or cellular immune responses, similar to that observed with SHIV89.6P infection of rhesus macaques. Infection with the CCR5-utilizing, rhesus macaque passaged, SHIVSF162P3 resulted in some overall CD4+ T cell decline, however, three of eight macaques naturally control SHIVSF162P3 viremia to very low levels in the setting of robust adaptive immunity. Despite attempts at infecting pigtail macaques with HIV-1 strains passaged in juvenile pigtail macaques in vivo or in PBMC isolated from pigtail macaques in vitro, only lower nonsustained levels of viral replication were observed. Our results provide a series of virologic models with which to evaluate potential AIDS vaccines in pigtail macaques.
A protective vaccine delivery system for in vivo T cell stimulation using nanoengineered polymer hydrogel capsules
Publisher: American Chemical Society (ACS)
Date: 13-10-2009
DOI: 10.1021/NN900715G
Abstract: Successful delivery of labile vaccine antigens, such as peptides and proteins, to stimulate CD4 and CD8 T cell immunity could improve vaccine strategies against chronic infections such as HIV and Hepatitis C. Layer-by-layer (LbL)-assembled nanoengineered hydrogel capsules represent a novel and promising technology for the protection and delivery of labile vaccine candidates to antigen-presenting cells (APCs). Here we report on the in vitro and in vivo immunostimulatory capabilities of LbL-assembled disulfide cross-linked poly(methacrylic acid) (PMA(SH)) hydrogel capsules as a delivery strategy for protein and peptide vaccines using robust transgenic mice models and ovalbumin (OVA) as a model vaccine. We demonstrate that OVA protein as well as multiple OVA peptides can be successfully encapsulated within nanoengineered PMA(SH) hydrogel capsules. OVA-containing PMA(SH) capsules are internalized by mouse APCs, resulting in presentation of OVA epitopes and subsequent activation of OVA-specific CD4 and CD8 T cells in vitro. OVA-specific CD4 and CD8 T cells are also activated to proliferate in vivo following intravenous vaccination of mice with OVA protein- and OVA peptide-loaded PMA(SH) hydrogel capsules. Furthermore, we show that OVA encapsulated within the PMA(SH) capsules resulted in at least 6-fold greater proliferation of OVA-specific CD8 T cells and 70-fold greater proliferation of OVA-specific CD4 T cells in vivo compared to the equivalent amount of OVA protein administered alone. These results highlight the potential of nanoengineered hydrogel capsules for vaccine delivery.
Immunological Principles Guiding the Rational Design of Particles for Vaccine Delivery
Publisher: American Chemical Society (ACS)
Date: 11-01-2017
Abstract: Despite the immense public health successes of immunization over the past century, effective vaccines are still lacking for globally important pathogens such as human immunodeficiency virus, malaria, and tuberculosis. Exciting recent advances in immunology and biotechnology over the past few decades have facilitated a shift from empirical to rational vaccine design, opening possibilities for improved vaccines. Some of the most important advancements include (i) the purification of subunit antigens with high safety profiles, (ii) the identification of innate pattern recognition receptors (PRRs) and cognate agonists responsible for inducing immune responses, and (iii) developments in nano- and microparticle fabrication and characterization techniques. Advances in particle engineering now allow highly tunable physicochemical properties of particle-based vaccines, including composition, size, shape, surface characteristics, and degradability. Enhanced collaborative efforts between researchers in immunology and materials science are expected to rise to next-generation vaccines. This process will be significantly aided by a greater understanding of the immunological principles guiding vaccine antigenicity, immunogenicity, and efficacy. With specific emphasis on PRR-targeted adjuvants and particle physicochemical properties, this review aims to provide an overview of the current literature to guide and focus rational particle-based vaccine design efforts.
CD4 + Target Cell Availability Determines the Dynamics of Immune Escape and Reversion In Vivo
Publisher: American Society for Microbiology
Date: 15-04-2008
DOI: 10.1128/JVI.02552-07
Abstract: Infections with human immunodeficiency virus (HIV) and the closely related monkey viruses simian-human immunodeficiency virus (SHIV) and simian immunodeficiency virus (SIV) are characterized by progressive waves of immune responses, followed by viral mutation and “immune escape.” However, escape mutation usually leads to lower replicative fitness, and in the absence of immune pressure, an escape mutant (EM) virus “reverts” to the wild-type phenotype. Analysis of the dynamics of immune escape and reversion has suggested it is a mechanism for identifying the immunogens best capable of controlling viremia. We have analyzed and modeled data of the dynamics of wild-type (WT) and EM viruses during SHIV infection of macaques. Modeling suggests that the dynamics of reversion and immune escape should be determined by the availability of target cells for infection. Consistent with this suggestion, we find that the rate of reversion of cytotoxic T-lymphocyte (CTL) EM virus strongly correlates with the number of CD4 + T cells available for infection. This phenomenon also affects the rate of immune escape, since this rate is determined by the balance of CTL killing and the WT fitness advantage. This analysis predicts that the optimal timing for the selection of immune escape variants will be immediately after the peak of viremia and that the development of escape variants at later times will lead to slower selection. This has important implications for comparative studies of immune escape and reversion in different infections and for identifying epitopes with high fitness cost for use as vaccine targets.
Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities
Publisher: Springer Science and Business Media LLC
Date: 29-05-2023
DOI: 10.1038/S41590-023-01508-Y
Abstract: High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4 + and CD8 + T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.
Vaccination after prior COVID-19 infection: Implications for dose sparing and booster shots
Publisher: Elsevier BV
Date: 10-2021
Improvement of immune dysregulation and health-related quality of life in individuals with long COVID at 24-months following SARS-CoV-2 infection
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.27.23294704
Abstract: This study investigated the humoral and cellular immune responses in in iduals with long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24-months. LC participants showed elevated spike and nucleocapsid IgG levels, higher neutralizing capacity, and increased spike- and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells at 3- and 8-months, but these differences did not persist at 24-months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at 24-month timepoint revealed similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC. No significant differences in exhaustion scores or antigen-specific T cell clones were observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24-months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count were associated with improvements in health-related quality of life.
Antibody-Dependent Cellular Cytotoxicity Responses to Seasonal Influenza Vaccination in Older Adults
Publisher: Oxford University Press (OUP)
Date: 02-11-2018
Abstract: Older adults are at high risk of influenza disease, but generally respond poorly to vaccination. Antibody-dependent cellular cytotoxicity (ADCC) may be an important component of protection against influenza infection. An improved understanding of the ADCC response to influenza vaccination in older adults is required. We studied sera s les from 3 groups of subjects aged ≥65 years (n = 16-17/group) receiving the 2008/2009 seasonal trivalent influenza vaccine (TIV). Subjects had minimal pre-existing hemagglutination inhibiting (HAI) antibodies and TIV induced either no, low, or high HAI responses. Serum ADCC activity was analyzed using Fc receptor cross-linking, NK cell activation, and influenza-infected cell killing. Most subjects from TIV nonresponder, low responder, and high responder groups had detectable ADCC antibodies prevaccination, but baseline ADCC was not predictive of HAI vaccine responsiveness. Interestingly, ADCC and HAI responses tracked closely across all groups, against all 3 TIV hemagglutinins, and in all ADCC assays tested. Older adults commonly have pre-existing ADCC antibodies in the absence of high HAI titers to circulating influenza strains. In older vaccinees, ADCC response mirrored HAI antibodies and was readily detectable despite high postvaccination HAI titers. Alternate measures of vaccine responsiveness and improved vaccinations in this at-risk group are needed.
Utility of Human Immunodeficiency Virus Type 1 Envelope as a T-Cell Immunogen
Publisher: American Society for Microbiology
Date: 12-2007
DOI: 10.1128/JVI.01408-07
Abstract: Human immunodeficiency virus (HIV)-specific CD8 T lymphocytes are important for the control of viremia, but the relative utility of responses to the various HIV proteins is controversial. Immune responses that force escape mutations that exact a significant fitness cost from the mutating virus would help slow progression to AIDS. The HIV envelope (Env) protein is subject to both humoral and cellular immune responses, suggesting that multiple rounds of mutation are needed to facilitate viral escape. The Gag protein, however, has recently been shown to elicit a more effective CD8 T-cell immune response in humans. We studied 30 pigtail macaques for their CD8 T-lymphocyte responses to HIV-1 Env and simian immunodeficiency virus (SIV) Gag following prime/boost vaccination and intrarectal challenge with simian-human immunodeficiency virus SHIV mn229 . Eight CD8 Env-specific T-cell epitopes were identified and mapped in 10 animals. Animals that generated Env-specific CD8 T-cell responses had equivalent viral loads and only a modest advantage in retention of peripheral CD4 T lymphocytes compared to those animals without responses to Env. This contrasts with animals that generated CD8 T-cell responses to SIV Gag in the same trial, demonstrating superior control of viral load and a larger advantage in retention of peripheral CD4 T cells than Gag nonresponders. Mutational escape was common in Env but, in contrast to mutations in Gag, did not result in the rapid emergence of dominant escape motifs, suggesting modest selective pressure from Env-specific T cells. These results suggest that Env may have limited utility as a CD8 T-cell immunogen.
Durable reprogramming of neutralizing antibody responses following Omicron breakthrough infection
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2023
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated in iduals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following Omicron BA.1 or BA.2 breakthrough infection, with longitudinal s ling up to 8 months after infection. Both BA.1 and BA.2 infections robustly boosted neutralization activity against the infecting strain while expanding breadth against BA.4, although neutralization activity was substantially reduced for the more recent XBB and BQ.1.1 strains. Cross-reactive memory B cells against both ancestral and Omicron spike were predominantly expanded by infection, with limited recruitment of de novo Omicron-specific B cells or antibodies. Modeling of neutralization titers predicts that protection from symptomatic reinfection against antigenically similar strains will be durable but is undermined by new emerging strains with further neutralization escape.
Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected Macaques
Publisher: Public Library of Science (PLoS)
Date: 03-11-2008
Lasting first impression: Pre-existing immunity restricts mucosal antibody responses during Omicron breakthrough
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2023
DOI: 10.1101/2023.03.28.23287848
Abstract: Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from: COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19 recovered vaccinees (convalescent, vaccinated) and in iduals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19 recovered vaccinees displayed improved antibody neutralizing activity, FcγR engagement and IgA compared to COVID-19 uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma. IgG, but not IgA, responses to breakthrough COVID-19 variants were d ened and narrowed by increased pre-existing vaccine-induced immunity to the ancestral strain. Salivary antibodies delayed initiation of boosting following breakthrough COVID-19 infection, especially Omicron BA.2, however, rose rapidly thereafter. Our data highlight how pre-existing immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
A recombinant avipoxvirus HIV-1 vaccine expressing interferon-gamma is safe and immunogenic in macaques
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1016/S0264-410X(99)00559-9
Abstract: Complex recombinant fowlpoxvirus (rFPV) vaccines expressing both HIV-1 antigens and type 1 cytokines could facilitate the induction of cellular immunity against HIV-1. A single rFPV expressing both HIV-1gag ol and human interferon-gamma (FPVgag ol-IFNgamma) was constructed and assessed as a therapeutic vaccine for safety and immunogenicity in macaques (Macaca nemestrina) previously infected with HIV-1. FPV gag ol-IFNgamma vaccinations were safe and enhanced T cell proliferative responses to Gag antigens (but not control tetanus antigens). Enhanced CTL responses to gag ol antigens were also observed following IFNgamma expressing vaccinations. Since cellular immunity may be critical to controlling or preventing HIV-1 infection, these observations suggest that avipox vectors co-expressing IFNgamma should be further evaluated as therapeutic or preventive HIV-1 vaccines.
Impact of HIV-1 viremia or sexually transmitted infection on semen-derived anti-HIV-1 antibodies and the immunosuppressive capacity of seminal plasma
Publisher: Wiley
Date: 13-11-2019
Abstract: Semen from HIV-1-infected men contains anti-HIV-1 antibodies and immunosuppressive factor(s). We assessed if suppression of viremia with antiretroviral therapy impacted seminal plasma immunosuppressive capacity or the Fc-dependent functions of seminal anti-HIV-1 antibodies. We also tested if active bacterial sexually transmitted infections altered the immunosuppressive capacity of seminal plasma.
Trivalent Live Attenuated Influenza-Simian Immunodeficiency Virus Vaccines: Efficacy and Evolution of Cytotoxic T Lymphocyte Escape in Macaques
Publisher: American Society for Microbiology
Date: 15-04-2013
DOI: 10.1128/JVI.02645-12
Abstract: There is an urgent need for a human immunodeficiency virus (HIV) vaccine that induces robust mucosal immunity. CD8 + cytotoxic T lymphocytes (CTLs) apply substantial antiviral pressure, but CTLs to in idual epitopes select for immune escape variants in both HIV in humans and SIV in macaques. Inducing multiple simian immunodeficiency virus (SIV)-specific CTLs may assist in controlling viremia. We vaccinated 10 Mane-A1 * 08401 + female pigtail macaques with recombinant influenza viruses expressing three Mane-A1 * 08401 -restricted SIV-specific CTL epitopes and subsequently challenged the animals, along with five controls, intravaginally with SIV mac251 . Seroconversion to the influenza virus vector resulted and small, but detectable, SIV-specific CTL responses were induced. There was a boost in CTL responses after challenge but no protection from high-level viremia or CD4 depletion was observed. All three CTL epitopes underwent a coordinated pattern of immune escape during early SIV infection. CTL escape was more rapid in the vaccinees than in the controls at the more dominant CTL epitopes. Although CTL escape can incur a “fitness” cost to the virus, a putative compensatory mutation 20 amino acids upstream from an immunodominant Gag CTL epitope also evolved soon after the primary CTL escape mutation. We conclude that vaccines based only on CTL epitopes will likely be undermined by rapid evolution of both CTL escape and compensatory mutations. More potent and possibly broader immune responses may be required to protect pigtail macaques from SIV.
Meibomian gland dropout is associated with immunodeficiency at HIV diagnosis: Implications for dry eye disease: Meibomian gland dropout in HIV individuals
Publisher: Elsevier BV
Date: 04-2020
Determinants of passive antibody efficacy in SARS-CoV-2 infection
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2022
DOI: 10.1101/2022.03.21.22272672
Abstract: A large number of studies have been carried out involving passive antibody administration for the treatment and prophylaxis of COVID-19 and have shown variable efficacy. However, the determinants of treatment effectiveness have not been identified. Here we aimed to aggregate all available data on randomised controlled trials of passive antibody treatment for COVID-19 to understand how the dose and timing affect treatment outcome. We analysed published studies of passive antibody treatment from inception to 7 January 2022 that were identified after searching various databases such as MEDLINE, Pubmed, ClinicalTrials.gov. We extracted data on treatment, dose, disease stage at treatment, and effectiveness for different clinical outcomes from these studies. To compare administered antibody levels between different treatments, we used data on in vitro neutralisation of pseudovirus to normalise the administered dose of antibody. We used a mixed-effects regression model to understand the relationship between disease stage at treatment and effectiveness. We used a logistic model to analyse the relationship between administered antibody dose (normalised to the mean convalescent titre) and outcome, and to predict efficacy of antibodies against different Omicron subvariants. We found that clinical stage at treatment was highly predictive of the effectiveness of both monoclonal antibodies and convalescent plasma therapy in preventing progression to subsequent stages (p .0001 and p=0.0089, respectively, chi-squared test). We also analysed the dose-response curve for passive antibody treatment of ambulant COVID-19 patients to prevent hospitalisation. Using this quantitative dose-response relationship, we predict that a number of existing monoclonal antibody treatment regimens should maintain clinical effectiveness in infection with currently circulating Omicron variants. Early administration of passive antibody therapy is crucial to achieving high efficacy in preventing clinical progression. A dose-response curve was derived for passive antibody therapy administered to ambulant symptomatic subjects to prevent hospitalisation. For many of the monoclonal antibody regimens analysed, the administered doses are estimated to be between 7 and fold higher than necessary to achieve 90% of the maximal efficacy against the ancestral (Wuhan-like) virus. This suggests that a number of current treatments should maintain high efficacy against Omicron subvariants despite reduction in in vitro neutralisation potency. This work provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. This work is supported by an Australian government Medical Research Future Fund awards GNT2002073 and MRF2005544 (to MPD, SJK), MRF2005760 (to MPD), an NHMRC program grant GNT1149990 (SJK and MPD), and the Victorian Government (SJK). SJK is supported by a NHMRC fellowship. DC, MPD, ZKM and EMW are supported by NHMRC Investigator grants and ZKM and EMW by an NHMRC Synergy grant (1189490). DSK is supported by a University of New South Wales fellowship. KLC is supported by PhD scholarships from Monash University, the Haematology Society of Australia and New Zealand and the Leukaemia Foundation. TT, HW and CB are members of the National COVID-19 Clinical Evidence Taskforce which is funded by the Australian Government Department of Health. We identified randomised controlled trials (RCTs) evaluating the effectiveness of SARS-CoV-2-specific neutralising monoclonal antibodies, hyperimmune immunoglobulin and convalescent plasma in the treatment of participants with a confirmed diagnosis of COVID-19 and in uninfected participants with or without potential exposure to SARS-CoV-2. The RCTs were identified from published searches conducted by the Cochrane Haematology living systematic review teams. A total of 37 randomised controlled trials (RCT) of passive antibody administration for COVID-19 were identified. This included 12 trials on monoclonal antibodies, 21 trials of convalescent plasma treatment, and 4 trials of hyperimmune globulin. These trials involved treatment of in iduals either prophylactically or at different stages of infection including post-exposure prophylaxis, symptomatic infection, and hospitalisation. The level of antibody administered ranged from a 250 ml volume of convalescent plasma through to 8 grams of monoclonal antibodies. Data for analysis was extracted from the original publications including dose and antibody levels of antibody administered, disease stage and timing of administration, primary outcome of study and whether they reported on our prespecified outcomes of interest, which include protection against symptomatic infection, hospitalisation, need for invasive mechanical ventilation (IMV) and death (all-cause mortality at 30 days). Our study included data across all 37 RCTs of passive antibody interventions for COVID-19 and aggregated the studies by the stage of infection at initiation of treatment. We found that prophylactic administration or treatment in earlier stages of infection had significantly higher effectiveness than later treatment. We also estimated the dose-response relationship between administered antibody dose and protection from progression from symptomatic ambulant COVID-19 to hospitalisation. We used this relationship to predict the efficacy of different monoclonal antibody treatment regimes against the Omicron subvariants BA.1, BA.2, and BA.4/5. We also used this dose-response relationship to estimate the maximal efficacy of monoclonal antibody therapy in the context of pre-existing endogenous neutralising antibodies. This work identifies that both prophylactic therapy and treatment in the early stages of symptomatic infection can achieve significant protection from infection or hospitalisation respectively. The dose-response relationship provides a quantitative means to predict the change in efficacy of different monoclonal antibodies against new variants and in semi-immune populations based on in vitro neutralisation data. We predict a number of existing monoclonal antibodies will be effective for preventing severe outcomes when administered early in BA.4/5 infections. It is likely that these therapies will provide little protection in in iduals with high levels of endogenous neutralising antibodies, such as healthy in iduals who have recently received a third dose of an mRNA vaccine.
Decay of Fc-dependent antibody functions after mild to moderate COVID-19
Publisher: Elsevier BV
Date: 06-2021
Importance of Fc-mediated functions of anti-HIV-1 broadly neutralizing antibodies
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
Evaluation in macaques of HIV-1 DNA vaccines containing primate CpG motifs and fowlpoxvirus vaccines co-expressing IFNγ or IL-12
Publisher: Elsevier BV
Date: 25-11-2004
DOI: 10.1016/J.VACCINE.2004.05.024
Abstract: Induction of HIV-specific T-cell responses by vaccines may facilitate efficient control of HIV. Plasmid DNA vaccines and recombinant fowlpoxvirus (rFPV) vaccines are promising HIV-1 vaccine candidates, although either vaccine alone may be insufficient to protect against HIV-1. A consecutive immunisation strategy involving priming with DNA and boosting with rFPV vaccines encoding multiple common HIV-1 antigens was further evaluated in 30 macaques. The DNA vaccine vector included CpG immunostimulatory molecules, and rFPV vaccines were compared with rFPV vaccines co-expressing the pro-T cell cytokines IFNgamma or IL-12. Vaccines expressed multiple HIV-1 genes, mutated to remove active sites of the HIV proteins. The vaccines were well tolerated, and a significant enhancement of DNA-vaccine primed HIV-1 specific T lymphocyte responses was observed following rFPV boosting. Co-expression of IFNgamma or IL-12 by the rFPV vaccines did not further enhance immune responses. Non-sterilising protection from a non-pathogenic HIV-1 challenge was observed. This study provides evidence of a safe, optimised, strategy for the generation of T-cell mediated immunity to HIV-1.
Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation
Publisher: Oxford University Press (OUP)
Date: 07-06-2015
DOI: 10.1111/CEI.12593
Abstract: Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been linked to protection from HIV infection and slower progression towards AIDS. However, antibody-dependent activation of NK cells results in phenotypical alterations similar to those observed on NK cells from in iduals with progressive HIV infection. Activation of NK cells induces matrix metalloproteinase (MMP)-mediated cleavage of cell surface CD16. In the present study we assessed the phenotype and functional profile of NK cells exhibiting post-activation MMP-mediated CD16 cleavage. We found that NK cells achieving the highest levels of activation during stimulation exhibit the most profound decreases in CD16 expression. Further, we observed that educated KIR3DL1+ NK cells from human leucocyte antigen (HLA)-Bw4-carrying donors exhibit larger decreases in CD16 expression post-activation than the KIR3DL1− NK cell subset containing cells educated via other inhibitory receptor/ligand combinations and non-educated NK cells. Lastly, we assessed the ex-vivo expression of CD16 on educated KIR3DL1+ NK cells and the KIR3DL1− NK cell subset from HLA-Bw4-carrying HIV-uninfected and HIV-infected donors. Suggestive of in-vivo activation of KIR3DL1+ NK cells during HIV infection, CD16 expression was higher on KIR3DL1+ than KIR3DL1− NK cells in uninfected donors but similar on both subsets in HIV-infected donors. These results are discussed in the context of how they may assist with understanding HIV disease progression and the design of immunotherapies that utilize antibody-dependent NK cell responses.
Robust and Prototypical Immune Responses towards Influenza Vaccines in the High-Risk Group of Indigenous Australians
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3781631
HIV Reactivation after Partial Protection by Neutralizing Antibodies
Publisher: Elsevier BV
Date: 05-2018
Abstract: It is widely thought that generating broadly neutralizing anti-HIV antibodies (BnAbs) will protect humans against HIV, given promising data from in vitro experiments and in vivo macaque studies. The primary action of BnAbs is preventing cell-free virus from entering cells. Recent in vitro and macaque data suggest that BnAbs are less potent against cell-associated virus exposure. We speculate that BnAb-based suppression of HIV transmission, particularly if mediated by cell-cell transmission, may result in some exposed subjects carrying a form of latent (or 'occult') HIV infection. Such largely hidden HIV infections may subsequently reactivate when BnAb levels decline. This concept has implications for the achievement of long-term sterilizing immunity to HIV.
Current and future nanoparticle vaccines for COVID-19
Publisher: Elsevier BV
Date: 12-2021
Integrated immune dynamics define correlates of COVID-19 severity and antibody responses
Publisher: Elsevier BV
Date: 03-2021
Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?
Publisher: Springer Science and Business Media LLC
Date: 28-04-2022
Prospects for antibody-based universal influenza vaccines in the context of widespread pre-existing immunity.
Publisher: Informa UK Limited
Date: 15-07-2015
DOI: 10.1586/14760584.2015.1068125
Abstract: Influenza inflicts significant global mortality and morbidity that can be combated by effective immunization. However, the protective efficacy of current vaccines is limited by both the significant antigenic ersity of the viral hemagglutinin protein and the capacity for rapid antigenic change. This necessitates global influenza surveillance efforts, frequent vaccine reformulation and annual readministration. There is, therefore, tremendous interest in the development of novel strategies to elicit broad and durable protection against both seasonal and pandemic infection. This review presents an overview of candidate universal influenza vaccines designed to elicit cross-protective antibody responses to hemagglutinin. In particular, we focus on the potential impact that widespread pre-existing influenza immunity may play upon the design, testing and deployment of universal influenza vaccines.
A paradigm for peptide vaccine delivery using viral epitopes encapsulated in degradable polymer hydrogel capsules
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BIOMATERIALS.2009.05.078
Abstract: We report on the use of degradable polymer capsules as carriers for the delivery of oligopeptide antigens to professional antigen presenting cells (APCs). To achieve encapsulation, oligopeptide sequences were covalently linked to a negatively charged carrier polymer via biodegradable linkages and the resulting conjugate was then adsorbed onto amine-functionalized silica particles. These peptide-coated particles were then used as templates for the layer-by-layer (LbL) deposition of thiolated poly(methacrylic acid) (PMA(SH)) and poly(vinylpyrrolidone) (PVPON) multilayers. Removal of the silica core and disruption of the hydrogen bonding between PMA(SH) and PVPON by altering the solution pH yielded disulfide-stabilized PMA capsules that retain the encapsulated cargo in an oxidative environment. In the presence of a natural reducing agent, glutathione, cleavage of the disulfide bonds causes release of the peptide from the capsules. The developed strategy provides control over peptide loading into polymer capsules and yields colloidally stable micron- and submicron-sized carriers with uniform size and peptide loading. The conjugation and encapsulation procedures were proven to be non-degrading to the peptide vaccines. The peptide-loaded capsules were successfully used to deliver their cargo to APCs and activate CD8 T lymphocytes in a non-human primate model of SIV infection ex vivo. The reported approach represents a novel paradigm in the delivery of peptide vaccines and other therapeutic agents.
Characterisation of macaque testicular leucocyte populations and T-lymphocyte immunity
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.JRI.2013.09.003
Abstract: The rodent testis is well established as a site of immune privilege where both innate and acquired immune responses are suppressed. Immune cells and responses within human or non-human primate testes, by contrast, are poorly characterised. This study used multi-colour flow cytometry to characterise the leukocytes in testicular cells isolated from 12 young adult pigtail macaques (Macaca nemestrina) by collagenase dispersal, and to measure the cytokine responses of macaque testicular T-lymphocytes to mitogens. B-lymphocytes and granulocytes were present in very low numbers (0.24% and 3.3% of leukocytes respectively), indicating minimal blood contamination. A median of 30.8% of the recovered testicular leukocytes were CD3+ lymphocytes, with CD4 and CD8 T-lymphocyte proportions similar to those in the blood. The proportion of naïve T-lymphocytes in the testis was low, with significantly higher frequencies of central memory cells, compared with the blood. A median of 42.7% of the testicular leukocytes were CD163+ macrophages, while 4.5% were CD14+CD163- monocyte-like macrophages. Small populations of myeloid and plasmacytoid dendritic cells, NK cells and NKT cells were also detected. Following mitogen stimulation, 19.7% of blood T-lymphocytes produced IFNγ and/or TNF, whereas significantly fewer (4.4%) of the testicular T-lymphocytes responded to stimulation. Our results characterise the immune cells within the adult macaque testis and identify a suppression of T-lymphocyte responses. This study provides a baseline to examine the immunology of the primate testis and suggests that testicular immune privilege could also be present in primates.
Measuring turnover of SIV DNA in resting CD4+ T cells using pyrosequencing: implications for the timing of HIV eradication therapies.
Publisher: Public Library of Science (PLoS)
Date: 07-04-2014
Development of a synthetic consensus sequence scrambled antigen HIV-1 vaccine designed for global use
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.VACCINE.2005.04.045
Abstract: Induction of high levels of broadly reactive cytotoxic T lymphocytes (CTL) remains a promising approach for an effective HIV-1 vaccine. We have developed a novel genetic-based vaccine strategy that encodes consensus overlapping peptide sets from all HIV-1 proteins scrambled together. This synthetic scrambled antigen vaccine (SAVINE) strategy has significant advantages, e.g. capacity to encode more antigens safely and is very flexible compared to traditional isolate-based strategies. The SAVINE vaccine strategy is clearly immunogenic, being able to restimulate a range of human HIV-1 specific responses in vitro and induce HIV-1 specific immunity in vivo in mice. Interestingly, different in vivo delivery strategies affected the resulting immunity and immunodominance pattern in mice. This platform strategy could be used for other infections and cancers where T cell responses are important for protection.
Protection afforded by live attenuated SIV is associated with rapid killing kinetics of CTLs
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1600-0684.2008.00326.X
Abstract: Live attenuated SIV vaccines are highly efficacious, but how they mediate protection is poorly understood. A feature of the effectiveness of live attenuated vaccines is their ability to control high dose challenge viruses early, without a large peak of acute viraemia. We hypothesized that long-lived antigen exposure from live attenuated SIV may result in CD8+ cytotoxic T lymphocytes persistently capable of rapidly cytolytic potential. We employed a kinetic degranulation assay to study multiple tetramer+ SIV-specific CTL specificities before and after the SIV(mac251) challenge of pigtail macaques inoculated with a live attenuated SIV. Live attenuated SIV-vaccinated animals rapidly controlled a subsequent challenge, with minimal viraemia after exposure. For over 9 months after the initial vaccination with live attenuated SIV we could detect both Gag- and Tat-specific CTLs that maintained a long-term capacity to rapidly degranulate (CD107a expression) and release granzyme B within 30 minutes of antigen exposure. This rapid cytolytic phenotype was maintained throughout the early period after challenge, despite the absence of a marked enhancement in CTL frequencies. Our results suggest that highly functional CTLs may contribute to the remarkable efficacy of live attenuated SIV vaccines. Studying the killing kinetics of CTLs induced by other, safer, HIV vaccines could facilitate a better understanding of the requirements for an effective HIV vaccine.
Identification of murine antigen-specific T follicular helper cells using an activation-induced marker assay.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JIM.2019.02.008
Abstract: Protective antibody (Ab) responses induced by natural infection or vaccination play a central role in defense against invasive pathogens. Germinal centers (GCs) are the sites of Ab affinity maturation and T follicular helper (Tfh) cells are a critical factor for driving GC formation and B cell selection. Therefore characterization of antigen (Ag)-specific Tfh cells is increasingly essential to define the mechanistic basis of protective antibody responses. However, since Tfh are weak producers of cytokines it is difficult to detect Ag-specific Tfh cells using conventional intracellular cytokine staining (ICS). Here, we report an assay identifying mouse Ag-specific Tfh cells by assessing the upregulation of surface activation-induced markers (AIM). Murine lymph node (LN)-derived Tfh cells largely retained CXCR5 and PD-1 expression following 18-hour cell culture. After influenza infection or influenza hemagglutinin (HA) protein vaccination of mice, stimulation of lymph node cell suspensions with peptide pools or whole protein drove upregulation of CD25, OX40 (CD134), ICOS (CD278) and CD154 on Tfh cells. Upregulation of either CD154 or CD25/OX40 proved a sensitive method for delineating HA-specific Tfh cells. This assay provides the opportunity to quantify antigen-specific Tfh cells in mice without the need for transgenic models or MHC-II tetramer reagents restricted to specific epitopes.
Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime-boost immunization
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1038/MI.2017.89
Abstract: Tissue-resident memory (T
Antibody mediated activation of natural killer cells in malaria exposed pregnant women
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41598-021-83093-4
Abstract: Immune effector responses against Plasmodium falciparum include antibody-mediated activation of innate immune cells, which can induce Fc effector functions, including antibody-dependent cellular cytotoxicity, and the secretion of cytokines and chemokines. These effector functions are regulated by the composition of immunoglobulin G (IgG) Fc N -linked glycans. However, a role for antibody-mediated natural killer (NK) cells activation or Fc N -linked glycans in pregnant women with malaria has not yet been established. Herein, we studied the capacity of IgG antibodies from pregnant women, with placental malaria or non-placental malaria, to induce NK cell activation in response to placental malaria-associated antigens DBL2 and DBL3. Antibody-mediated NK cell activation was observed in pregnant women with malaria, but no differences were associated with susceptibility to placental malaria. Elevated anti-inflammatory glycosylation patterns of IgG antibodies were observed in pregnant women with or without malaria infection, which were not seen in healthy non-pregnant controls. This suggests that pregnancy-associated anti-inflammatory Fc N -linked glycans may d en the antibody-mediated activation of NK cells in pregnant women with malaria infection. Overall, although anti-inflammatory glycans and antibody-dependent NK cell activation were detected in pregnant women with malaria, a definitive role for these antibody features in protecting against placental malaria remains to be proven.
HIV Infection Abrogates the Functional Advantage of Natural Killer Cells Educated through KIR3DL1/HLA-Bw4 Interactions To Mediate Anti-HIV Antibody-Dependent Cellular Cytotoxicity
Publisher: American Society for Microbiology
Date: 15-04-2012
DOI: 10.1128/JVI.06112-11
Abstract: Combinations of KIR3DL1 and HLA-Bw4 alleles protect against HIV infection and/or disease progression. These combinations enhance NK cell responsiveness through the ontological process of education. However, educated KIR3DL1 + NK cells do not have enhanced degranulation upon direct recognition of autologous HIV-infected cells. Since antibody-dependent cellular cytotoxicity (ADCC) is associated with improved HIV infection outcomes and NK cells overcome inhibition through killer cell immunoglobulin-like receptors (KIR) to mediate ADCC, we hypothesized that KIR3DL1-educated NK cells mediate anti-HIV ADCC against autologous cells. A whole-blood flow cytometry assay was used to evaluate ADCC-induced activation of NK cells. This assay assessed activation (gamma interferon [IFN-γ] production and/or CD107a expression) of KIR3DL1 + and KIR3DL1 − NK cells, from HLA-Bw4 + and HLA-Bw4 − HIV-positive and HIV-negative in iduals, in response to autologous HIV-specific ADCC targets. KIR3DL1 + NK cells were more functional than KIR3DL1 − NK cells from HLA-Bw4 + , but not HLA-Bw4 − , healthy controls. In HIV-infected in iduals, no differences in NK cell functionality were observed between KIR3DL1 + and KIR3DL1 − NK cells in HLA-Bw4 + in iduals, consistent with dysfunction of NK cells in the setting of HIV infection. Reflecting the partial normalization of NK cell responsiveness following initiation of antiretroviral therapy, a significant correlation was observed between the peripheral CD4 + T-lymphocyte counts in antiretroviral therapy-treated subjects and the functionality of NK cells. However, peripheral CD4 + T-lymphocyte counts were not correlated with an anti-HIV ADCC functional advantage in educated KIR3DL1 + NK cells. The abrogation of the functional advantage of educated NK cells may enhance HIV disease progression. Strategies to enhance the potency of NK cell-mediated ADCC may improve HIV therapies and vaccines.
NK Cell Function and Antibodies Mediating ADCC in HIV-1-Infected Viremic and Controller Patients
Publisher: Mary Ann Liebert Inc
Date: 10-2011
Abstract: Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the FcγRIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were ided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-γ expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.
Vorapaxar for HIV-associated inflammation and coagulopathy (ADVICE): a randomised, double-blind, placebo-controlled trial
Publisher: Elsevier BV
Date: 10-2018
Moving the HIV vaccine field forward: concepts of protective immunity
Publisher: Elsevier BV
Date: 06-2019
What level of neutralising antibody protects from COVID-19?
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2021
DOI: 10.1101/2021.03.09.21252641
Abstract: Both previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
The role of HIV-specific antibody-dependent cellular cytotoxicity in HIV prevention and the influence of the HIV-1 Vpu protein
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2015
The maturation of antibody technology for the HIV epidemic
Publisher: Wiley
Date: 06-05-2014
DOI: 10.1038/ICB.2014.35
Abstract: Antibodies are one of our most useful biological tools. Indeed, improvements in antibody-based technologies have ushered in a new era of antibody-based therapeutics, research and diagnostic tools. Although improved technologies have led to the development of therapeutic antibodies for treatment of malignancies and inflammatory conditions, the use of advanced antibody technology in the therapy of viral infections is in its infancy. Non-human primate studies have demonstrated that antibodies against the HIV envelope can both prevent viral infection and control viremia. Despite the obvious potential of antibody therapies against HIV, there remain limitations in production and purification capacity that require further research. Recent advances in recombinant antibody technology have led to the development of a range of novel antibody fragments, such as single-domain nanobodies and bispecific antibodies, that are capable of targeting cancer cells to cytotoxic T cells. Novel antibody production techniques have also been designed, allowing antibodies to be obtained from non-mammalian cells, bovine colostrum and the periplasm and cytoplasm of bacteria. These advances may allow large-scale production of HIV antibodies that are capable of protecting against HIV infection or serving as therapeutics that reduce the need for life-long antiretroviral treatment. This review summarises recent advances in antibody-based technologies and discusses the possibilities and challenges of using these advances to design prophylactics and therapeutics against HIV.
Re: Integrated Immune Dynamics Define Correlates of COVID-19 Severity and Antibody Responses
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3701261
Characterization of Key Bio–Nano Interactions between Organosilica Nanoparticles and Candida albicans
Publisher: American Chemical Society (ACS)
Date: 04-09-2019
Abstract: Nanoparticle-cell interactions between silica nanomaterials and mammalian cells have been investigated extensively in the context of drug delivery, diagnostics, and imaging. While there are also opportunities for applications in infectious disease, the interactions of silica nanoparticles with pathogenic microbes are relatively underexplored. To bridge this knowledge gap, here, we investigate the effects of organosilica nanoparticles of different sizes, concentrations, and surface coatings on surface association and viability of the major human fungal pathogen
Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41591-021-01377-8
Abstract: Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Prime-Boost Vaccination: Impact on the HIV-1 Vaccine Field
Publisher: Elsevier
Date: 2015
An escape clock for estimating the turnover of SIV DNA in resting CD4⁺ T cells.
Publisher: Public Library of Science (PLoS)
Date: 05-04-2012
Influence of Poly(ethylene glycol) Molecular Architecture on Particle Assembly and Ex Vivo Particle–Immune Cell Interactions in Human Blood
Publisher: American Chemical Society (ACS)
Date: 19-05-2021
Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1038/S41467-021-21444-5
Abstract: The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with in idual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4 + and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG + memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.
A Minimally Replicative HIV-2 Live-Virus Vaccine ProtectsM. nemestrinafrom Disease after HIV-2287Challenge
Publisher: Elsevier BV
Date: 03-1998
Abstract: M. nemestrina immunized with an apathogenic HIV-2 molecular clone (HIV-2KR) were protected from CD4 decline and disease upon challenge with HIV-2(287), after any immunizing virus could be detected. Higher but not lower inocula of HIV-2KR were protective against intravenous inoculation of either 10(5) or 10(1) TCID50 of HIV-2(287). Protected animals displayed substantial reductions in PBMC proviral burden (1-3 logs), viral titers (1-2 logs), and plasma viral RNA (2-4 logs) compared to unprotected or naive animals as early as 1 week postinfection. Plasma viral RNA became undetectable after 24 weeks in protected animals, but remained high in unprotected animals. No viral RNA was present in the spleen of the protected animal necropsied more than a year after challenge (though viral DNA was still present). No neutralizing responses could be demonstrated, but CTL activity was detected sooner and at higher levels after challenge in protected than in unprotected macaques. In this novel HIV-2 vaccine model, protection was clearly dose-dependent, and clearance of challenge virus RNA from the plasma did not require detectable ongoing replication of the immunizing virus at the time of challenge.
Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2022
DOI: 10.1038/S41590-021-01113-X
Abstract: A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied in iduals with LC compared to age- and gender-matched recovered in iduals without LC, unexposed donors and in iduals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Antibody-Dependent Cellular Cytotoxicity Is Associated with Control of Pandemic H1N1 Influenza Virus Infection of Macaques
Publisher: American Society for Microbiology
Date: 15-05-2013
DOI: 10.1128/JVI.03030-12
Abstract: Emerging influenza viruses pose a serious risk to global human health. Recent studies in ferrets, macaques, and humans suggest that seasonal H1N1 (sH1N1) infection provides some cross-protection against 2009 pandemic influenza viruses (H1N1pdm), but the correlates of cross-protection are poorly understood. Here we show that seasonal infection of influenza-naïve Indian rhesus macaques ( Macaca mulatta ) with A/Kawasaki/173/2001 (sH1N1) virus induces antibodies capable of binding the hemagglutinin (HA) of both the homologous seasonal virus and the antigenically ergent A/California/04/2009 (H1N1pdm) strain in the absence of detectable H1N1pdm-specific neutralizing antibodies. These influenza virus-specific antibodies activated macaque NK cells to express both CD107a and gamma interferon (IFN-γ) in the presence of HA proteins from either sH1N1 or H1N1pdm viruses. Although influenza virus-specific antibody-dependent cellular cytotoxicity (ADCC)-mediated NK cell activation diminished in titer over time following sH1N1 infection, these cells expanded rapidly within 7 days following H1N1pdm exposure. Furthermore, we found that influenza virus-specific ADCC was present in bronchoalveolar lavage fluid and was able to activate lung NK cells. We concluded that infection with a seasonal influenza virus can induce antibodies that mediate ADCC capable of recognizing ergent influenza virus strains. Cross-reactive ADCC may provide a mechanism for reducing the severity of ergent influenza virus infections.
Vaccines and Vaccine Strategies Against HIV
Publisher: Bentham Science Publishers Ltd.
Date: 2004
Abstract: The HIV/AIDS pandemic is a global emergency and a preventive HIV vaccine is urgently needed. HIV has, however, proved a difficult pathogen to vaccinate against. This is largely because HIV has a very high mutation rate and can escape immune responses, it has a latent stage where it can rest silently integrated into host DNA, and neutralising antibodies that can neutralise erse field strains have so far proved difficult to induce. There is however, considerable evidence now that HIV-specific CD4 and CD8 T cells can provide partial control of HIV replication and delay or prevent disease. Technologies to quantify and analyse HIV-specific T cells have advanced recently, and in particular ELISpot, intracellular cytokine staining and tetramer studies have provided clear analyses of the ability of HIV vaccines to induce T cell responses. The use of pools of overlapping HIV peptides as in vitro antigens has also provided a standardised reagent for accurate measurement of T cell responses. HIV protein vaccines have not induced broad neutralising antibodies or T cell responses and failed to protect humans in the only phase III efficacy trial yet completed. Viral vectors, such as canarypox, engineered to express HIV genes, have induced HIV-specific CD8 T cell responses in a minority of subjects in phase II trials and are proceeding to human efficacy trials. Currently, the most effective method of inducing CD8+ CTL immunity in non-human primates utilises priming with naked plasmid DNA and then boosting with recombinant viral vectors both encoding various parts of the HIV genome. Such vaccines have induced non-sterilising immunity to virulent Simian/Human immunodeficiency virus exposure in macaques and have entered phase I trials. Multiple other approaches are also being evaluated in what has become a global effort for a vaccine to prevent AIDS. Although an HIV vaccine is still a long way off, there is reason to be optimistic that a vaccine to prevent AIDS will eventually be developed.
Characteristics of effective immune control of simian/human immunodeficiency virus in pigtail macaques
Publisher: Mary Ann Liebert Inc
Date: 2006
Abstract: Considerable evidence suggests both HIV-specific T cells and neutralizing antibodies (nAb) can, separately, assist control of viremia. T cell and nAb responses were studied in detail in three pigtail macaques protected from chronic simian/human immunodeficiency virus (SHIV) viremia by DNA prime/fowlpoxvirus boost vaccine regimens. Immunity was studied both after an initial intrarectal SHIV challenge, as well as during CD8 T cell depletion and a subsequent intravenous SHIV rechallenge. Remarkably, SHIV-specific CD4 and CD8 T cells were detectable in the absence of viremia following an initial SHIV challenge in one animal, subsequent to recovery from CD8 T cell depletion in all three animals, and following control of heterologous SHIV rechallenge in two animals. Neutralizing antibodies were also enhanced following CD8 depletion without recrudescence of viremia in all three animals. These observations, although in a small subset of animals, suggest the hypothesis that combinations of primed T cell immunity and neutralizing antibodies can maintain control of chronic primate lentiviral infections.
Immunological basis for enhanced immunity of nanoparticle vaccines
Publisher: Informa UK Limited
Date: 14-02-2019
DOI: 10.1080/14760584.2019.1578216
Abstract: Immunization has been a remarkably successful public health intervention however, new approaches to vaccine design are essential to counter existing and emerging infectious diseases which have defied traditional vaccination efforts to date. Nanoparticles (ordered structures with dimensions in the range of 1-1000 nm) have great potential to supplement traditional vaccines based upon pathogen subunits, or killed or attenuated microorganisms, as exemplified by the successful licensure of virus-like particle vaccines for human papillomavirus and hepatitis B. However, the immunological mechanisms that underpin the potent immunity of nanoparticle vaccines are poorly defined. Here, we review the immunity of nanoparticle immunization. The display of antigen in a repetitive, ordered array mimics the surface of a pathogen, as does their nanoscale size. These properties facilitate enhanced innate immune activation, improved drainage and retention in lymph nodes, stronger engagement with B cell receptors, and augmented T cell help in driving B cell activation. In the near future, increasingly complex nanoparticle vaccines displaying multiple antigens and/or co-delivered adjuvants will reach clinical trials. An improved mechanistic understanding of nanoparticle vaccination will ultimately facilitate the rational design of improved vaccines for human health.
Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination
Publisher: Frontiers Media SA
Date: 20-12-2017
Mucosal-associated invariant T cells are depleted and exhibit altered chemokine receptor expression and elevated granulocyte macrophage-colony stimulating factor production during end-stage renal disease
Publisher: Frontiers Media SA
Date: 17-05-2018
Person-Specific Biomolecular Coronas Modulate Nanoparticle Interactions with Immune Cells in Human Blood
Publisher: American Chemical Society (ACS)
Date: 28-10-2020
Determining the immune mechanisms of protection from AIDS: correlates of immunity and the development of syngeneic macaques
Publisher: Wiley
Date: 10-2001
DOI: 10.1034/J.1600-065X.2001.1830108.X
Abstract: The AIDS pandemic is a global emergency and a preventive vaccine is urgently needed. CD4 and CD8 T-cell responses appear important in controlling human immunodeficiency virus (HIV)-1 in humans and simian immunodeficiency virus (SIV) in macaques. The utility of vaccines that induce high levels of SIV- or HIV-specific T cells has recently become clearer. Since T cells recognize virus-infected cells rather than free virus, T-cell-based vaccines only have the capacity to control infections (non-sterilizing immunity) and to prevent continuing or persisting infection. An HIV/SIV infection of macaques that is partially controlled by vaccine-induced T-cell responses permits a critical window of opportunity for the efficient generation and recruitment of additional T- and B-cell immune responses to the incoming viral inoculum. Although CD8-depletion experiments in macaques have defined the utility of CD8 T responses in control of SIV infections in macaques, direct evidence on the utility of either CD4 or CD8 T-cell responses in protective immunity to SIV following vaccination is lacking. The availability of genetically identical macaques would allow cell transfer studies and help define with more certainty the role of cellular immune responses in protection from AIDS. The review also focuses on the development of syngeneic macaques by twinning and cloning technologies.
Dimeric Fcγ Receptor Enzyme-Linked Immunosorbent Assay To Study HIV-Specific Antibodies: A New Look into Breadth of Fcγ Receptor Antibodies Induced by the RV144 Vaccine Trial
Publisher: The American Association of Immunologists
Date: 15-07-2017
Abstract: Ab-dependent cellular cytotoxicity (ADCC) responses are of growing interest in the HIV vaccine field but current cell-based assays are usually difficult to reproduce across laboratories. We developed an ELISA and multiplex assay to model the cross-linking of Fcγ receptors (FcγR) by Abs, which is required to initiate an ADCC response. Our FcγR dimer ELISA readily detected Abs in s les from two separate cohorts of the partially efficacious Thai RV144 HIV vaccine efficacy trial. The FcγR dimer–binding Abs induced by the RV144 regimen correlated well with a functional measure of ADCC as well as IgG subclasses. The high-throughput multiplex assay allowed us to simultaneously measure FcγR dimer–binding Abs to 32 different HIV Ags, providing a measure of the breadth of FcγR-binding Abs induced by the RV144 trial. FcγR-binding Abs specific to V regions 1 and 2 were strongly associated with increased breadth of recognition of different Env proteins, suggesting anti–V regions 1 and 2 Abs may be a marker of ADCC breadth. This FcγR dimer provides an important tool for the further analysis and refinement of ADCC-inducing HIV and other antiviral vaccine regimens.
Characterization of the Kynurenine pathway and quinolinic acid production in macaque macrophages
Publisher: SAGE Publications
Date: 2012
DOI: 10.4137/IJTR.S11789
Abstract: The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation.
Influenza lineage extinction during the COVID-19 pandemic?
Publisher: Springer Science and Business Media LLC
Date: 28-09-2021
Listeria monocytogenes peritonitis with review of literature
Publisher: Wiley
Date: 08-1994
Knowns and Unknowns of Assaying Antibody-Dependent Cell-Mediated Cytotoxicity Against HIV-1
Publisher: Frontiers Media SA
Date: 10-05-2019
Can HIV-1-Specific ADCC Assist the Clearance of Reactivated Latently Infected Cells?
Publisher: Frontiers Media SA
Date: 27-05-2015
Inducible Bronchus-Associated Lymphoid Tissues (iBALT) Serve as Sites of B Cell Selection and Maturation Following Influenza Infection in Mice
Publisher: Frontiers Media SA
Date: 29-03-2019
Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine
Publisher: The American Association of Immunologists
Date: 15-07-2014
Abstract: There is an urgent need for universal influenza vaccines that can control emerging pandemic influenza virus threats without the need to generate new vaccines for each strain. Neutralizing Abs to the influenza virus hemagglutinin glycoprotein are effective at controlling influenza infection but generally target highly variable regions. Abs that can mediate other functions, such as killing influenza-infected cells and activating innate immune responses (termed “Ab-dependent cellular cytotoxicity [ADCC]-mediating Abs”), may assist in protective immunity to influenza. ADCC-mediating Abs can target more conserved regions of influenza virus proteins and recognize a broader array of influenza strains. We review recent research on influenza-specific ADCC Abs and their potential role in improved influenza-vaccination strategies.
NKT cell depletion in humans during early HIV infection
Publisher: Wiley
Date: 29-04-2014
DOI: 10.1038/ICB.2014.25
Abstract: Natural killer T (NKT) cells bridge across innate and adaptive immune responses and have an important role in chronic viral infections such as human immunodeficiency virus (HIV). NKT cells are depleted during chronic HIV infection, but the timing, drivers and implications of this NKT cell depletion are poorly understood. We studied human peripheral blood NKT cell levels, phenotype and function in 31 HIV-infected subjects not on antiretroviral treatment from a mean of 4 months to 2 years after HIV infection. We found that peripheral CD4(+) NKT cells were substantially depleted and dysfunctional by 4 months after HIV infection. The depletion of CD4(+) NKT cells was more marked than the depletion of total CD4(+) T cells. Further, the early depletion of NKT cells correlated with CD4(+) T-cell decline, but not HIV viral levels. Levels of activated CD4(+) T cells correlated with the loss of NKT cells. Our studies suggest that the early loss of NKT cells is associated with subsequent immune destruction during HIV infection.
Modulating the Selectivity and Stealth Properties of Ellipsoidal Polymersomes through a Multivalent Peptide Ligand Display
Publisher: Wiley
Date: 19-05-2020
Epitope-specific CD8+ T cell kinetics rather than viral variability determine the timing of immune escape in simian immunodeficiency virus infection.
Publisher: The American Association of Immunologists
Date: 05-2015
Abstract: CD8+ T cells are important for the control of chronic HIV infection. However, the virus rapidly acquires “escape mutations” that reduce CD8+ T cell recognition and viral control. The timing of when immune escape occurs at a given epitope varies widely among patients and also among different epitopes within a patient. The strength of the CD8+ T cell response, as well as mutation rates, patterns of particular amino acids undergoing escape, and growth rates of escape mutants, may affect when escape occurs. In this study, we analyze the epitope-specific CD8+ T cells in 25 SIV-infected pigtail macaques responding to three SIV epitopes. Two epitopes showed a variable escape pattern and one had a highly monomorphic escape pattern. Despite very different patterns, immune escape occurs with a similar delay of on average 18 d after the epitope-specific CD8+ T cells reach 0.5% of total CD8+ T cells. We find that the most delayed escape occurs in one of the highly variable epitopes, and that this is associated with a delay in the epitope-specific CD8+ T cells responding to this epitope. When we analyzed the kinetics of immune escape, we found that multiple escape mutants emerge simultaneously during the escape, implying that a erse population of potential escape mutants is present during immune selection. Our results suggest that the conservation or variability of an epitope does not appear to affect the timing of immune escape in SIV. Instead, timing of escape is largely determined by the kinetics of epitope-specific CD8+ T cells.
Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections.
Publisher: American Society for Clinical Investigation
Date: 22-09-2023
Antibody-dependent phagocytosis (ADP) responses following trivalent inactivated influenza vaccination of younger and older adults
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.VACCINE.2017.09.062
Abstract: Globally the most commonly utilised immunisation against influenza is the trivalent inactivated influenza vaccine (TIV) derived from an A/H1N1, an A/H3N2 and aB type influenza virus. Vaccine effectiveness of TIV varies year to year, depending on how well antigenically matched the strains in the vaccine are compared to circulating strains [1,2]. Moreover, vaccine effectiveness can vary within certain subpopulations such as HIV-positive, young children and the elderly. Decreased vaccine effectiveness in the elderly is associated with impaired Ab production, as measured by standard hemagglutination inhibition (HAI) assays. We investigated the level of Antibody Dependent Phagocytosis (ADP)-mediating Abs induced by the 2008-TIV in healthy Australian adults aged over and under 60years to determine if this immune function was also reduced in the elderly. We utilised an ADP assay that measures the uptake of IgG-opsonised HA-coated fluorescent microspheres by a monocytic cell line. We also measured HA-specific Abs that are close enough to bind to dimeric FcγRIIa ectodomains in an ELISA-based assay. Furthermore, we compared the extent of cross-reactive recognition of erse influenza strains by ADP-mediating Abs found in pre- and post-vaccination sera in both of these groups. We found that young adults and older adults mounted similar ADP activity against HAs contained in the 2008-TIV, despite older adults have diminished HI responses. The level of cross-reactive antibodies against other HAs was limited in both groups. We conclude that seasonal influenza vaccination elicits limited cross-reactive ADP to HA in both young and older adults. New influenza vaccination strategies that elicit cross-reactive and polyfunctional antibodies are needed.
Impact of anti-PEG antibodies induced by SARS-CoV-2 mRNA vaccines
Publisher: Springer Science and Business Media LLC
Date: 20-12-2022
Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: A systematic review and meta-analysis
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2023
DOI: 10.1101/2023.06.18.23291566
Abstract: Surrogates of antiviral efficacy are needed for COVID-19. We investigated the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in unvaccinated outpatients treated for mild to moderate COVID-19. We searched PubMed, Scopus and medRxiv from inception to 27 th September 2022, for randomised controlled trials (RCTs) which tested potential treatments for COVID-19 in non-hospitalized patients. We included studies that reported both clinical and virological outcomes. Clinical outcomes were the rate of disease progression (generally hospitalization or death within 28 days of commencing treatment) and virological outcomes were viral load (viral RNA copies in upper respiratory tract swabs) within the first 7 days of treatment. Studies were excluded if they did not report on the outcome of a primary randomised controlled trial, or if results were reported in a more complete form in another publication. Risk of Bias assessment was performed using the RoB 2.0 tool. We used generalised linear models with random effects to assess the association between outcomes and account for study heterogeneity. We identified 1372 unique studies of which 14 (with a total of 9257 participants) met inclusion criteria. Larger virological treatment effects at both day 3 and day 5 were associated with decreased odds of progression to hospitalisation or death in unvaccinated ambulatory subjects. The odds ratio (OR) for each extra two-fold reduction in viral load in treated compared to control subjects was 0.54 on both days 3 and 5 post treatment (day 3 95% CI 0.38 to 0.74, day 5 95%CI 0.41 to 0.72). There was no relationship between the odds of hospitalisation or death and virological treatment effect at day 7 (OR 0.91, 95%CI 0.74 to 1.13). This review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a surrogate of clinical efficacy to prevent hospitalisation with COVID-19. Limitations included the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes. These findings support the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy. The authors were supported by the Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council and the University of New South Wales.
Delivery of immunotherapy with peptide-pulsed blood in macaques
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.VIROL.2008.06.006
Abstract: Simple and effective delivery methods for cellular immunotherapies are needed. We assessed ex vivo pulsing of overlapping SIV Gag 15mer peptides onto either whole blood or PBMC in 15 randomly assigned SIV-infected macaques. Both delivery methods were safe and immunogenic, stimulating high levels of broad and polyfunctional Gag-specific CD4 and CD8 T cells. Delivery of overlapping Gag peptides via either whole blood or PBMC is suitable for clinical evaluation.
Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression
Publisher: The American Association of Immunologists
Date: 2014
Abstract: There is much interest in the potential of Ab-dependent cellular cytotoxicity (ADCC) to slow disease progression following HIV infection. Despite several studies demonstrating a positive association between ADCC and slower disease progression, it is possible that continued stimulation of NK cells by ADCC during chronic HIV infection could render these cells dysfunctional. Indeed, activation of NK cells by ADCC results in matrix metalloproteinase–induced reductions in CD16 expression and activation refractory periods. In addition, ex vivo analyses of NK cells from HIV-infected in iduals revealed other alterations in phenotype, such as decreased expression of the activating NKp46 receptor that is essential for NK-mediated antitumor responses and immunity from infection. Because NKp46 shares a signaling pathway with CD16, we hypothesized that activation-induced downregulation of both receptors could be controlled by a common mechanism. We found that activation of NK cells by anti-HIV or anti-CD16 Abs resulted in NKp46 downregulation. The addition of a matrix metalloproteinase inhibitor attenuated NKp46 downregulation following NK cell activation by anti-HIV Abs. Consequently, these results suggest that continued stimulation through CD16 has the potential to impair natural cytotoxicity via attenuation of NKp46-dependent signals.
At Least Three Doses of Leading Vaccines Essential for Neutralisation of SARS-CoV-2 Omicron Variant
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2022
DOI: 10.1101/2022.02.20.22271237
Abstract: Plasma s les taken at different time points from donors who received either AstraZeneca (Vaxzevria) or Pfizer (Comirnaty) or Moderna (Spikevax) coronavirus disease-19 (COVID-19) vaccine were assessed in virus neutralization assays against Delta and Omicron variants of concern and a reference isolate (VIC31). With the Pfizer vaccine there was 6-8-fold reduction in 50% neutralizing antibody titres (NT 50 ) against Delta and VIC31 at 6 months compared to 2 weeks after the second dose followed by 25-fold increase at 2 weeks after the third dose. Neutralisation of Omicron was only consistently observed 2 weeks after the third dose, with most s les having titres below the limit of detection at earlier timepoints. Moderna results were similar to Pfizer at 2 weeks after the second dose, while the titres for AstraZeneca s les derived from older donors were 7-fold lower against VIC31 and below the limit of detection against Delta and Omicron. Age and gender were not found to significantly impact our results. These findings indicate that vaccine matching may be needed, and that at least a third dose of these vaccines is necessary to generate sufficient neutralising antibodies against emerging variants of concern, especially Omicron, amidst the challenges of ensuring vaccine equity worldwide.
Atypical B cells are a normal component of immune responses to vaccination and infection in humans
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.28.120808
Abstract: The full ersity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naïve and memory B cells, there exists a population of CD11c + , CD27 − CD21 − “atypical” B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the ersity of both antigen-specific B cells and total B cells in healthy subjects and in iduals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed in iduals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy in iduals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.
Suboptimal SARS-CoV-2−specific CD8 + T cell response associated with the prominent HLA-A*02:01 phenotype
Publisher: Proceedings of the National Academy of Sciences
Date: 10-09-2020
Abstract: As the recall of CD8 + T cell memory promotes rapid recovery in, for ex le, influenza, we investigated circulating SARS-CoV-2−specific CD8 + T cells from COVID-19 patients. For two HLA-A*02:01 SARS-CoV-2−specific CD8 + T cell epitopes, we found that, while ex vivo frequencies of responding T cells were approximately fivefold higher than for pre−COVID-19 s les, they were ∼10-fold lower than for influenza or EBV-specific memory CD8 + T cells. Additionally, SARS-CoV-2−specific CD8 + T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes. Might this unexpectedly low prevalence of classical effector memory T cells be a negative consequence of the infectious process that could be avoided by prior priming with an appropriately constituted vaccine?
Substantial envelope-specific CD8 T-cell immunity fails to control siv disease
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.VIROL.2008.11.030
Abstract: It is unknown which HIV proteins to target by vaccination in order to generate the most effective CD8 T-cell immunity. We recently immunized SIV(mac251)-infected pigtail macaques with Gag peptides or a cocktail of peptides spanning all SIV proteins, including SIV Env. High-level SIV Env-specific CD8 T-cell responses were generated and 7 novel Env-specific CD8 T-cell epitopes in 10 animals were mapped. Env-specific CD8 T-cell responses were significantly inferior to Gag-specific responses, and no better than unvaccinated control animals, in the control of SIV replication and prevention of disease. Escape mutations emerged within several Env-specific CTL epitopes, suggesting at least some pressure imparted by the Env CTL responses, but this did not correlate with significantly reduced SIV replication. We conclude Env-specific CTL may not be the most effective response to induce by vaccination.
Subtype AE HIV-1 DNA and recombinant Fowlpoxvirus vaccines encoding five shared HIV-1 genes: Safety and T cell immunogenicity in macaques
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.VACCINE.2004.10.012
Abstract: To induce broad T cell immunity to HIV-1, we evaluated the safety, immunogenicity and dose-response relationship of DNA and recombinant Fowlpoxvirus (rFPV) vaccines encoding five shared HIV subtype AE genes (Gag, Pol, Env, Tat, Rev) in pigtail macaques. The DNA (three doses of either 1 mg or 4.5 mg) and rFPV (a single boost of either 5 x 10(7) or 2 x 10(8) plaque forming units) vaccines were administered intramuscularly without adjuvants. Broadly reactive HIV-specific T cell immunity was stimulated by all doses of the vaccines administered, without significant differences between the high and low doses studied. The vaccines induced both CD4 and CD8 T cell responses to Gag, Pol, Env and Tat/Rev proteins, with CD4 T cell responses being greater in magnitude than CD8 T cell responses. The vaccine-induced T cell responses had significant cross-recognition of heterologous HIV-1 proteins from non-AE HIV-1 subtypes. In conclusion, these subtype AE HIV-1 DNA and rFPV vaccines were safe, induced broad T-cell immunity in macaques, and are suitable for progression into clinical trials.
Influenza B viruses: underestimated and overlooked
Publisher: CSIRO Publishing
Date: 06-09-2021
DOI: 10.1071/MA21033
Abstract: Influenza B viruses circulate globally every year causing respiratory disease with significant clinical and socio-economic impacts. IBV are considered exclusive human pathogens with no established animal reservoirs, which suggests with concerted effort it may be possible to eradicate this virus from human circulation. However, this requires a deeper understanding of IBV virology and immunology and the design of vaccines that induce universal immunity to antigenic variants of IBV.
Screening and confirmatory testing of MHC class i alleles in pig-tailed macaques
Publisher: Springer Science and Business Media LLC
Date: 10-05-2011
DOI: 10.1007/S00251-011-0529-5
Abstract: Pig-tailed macaques (Macaca nemestrina) are a commonly studied primate model of human AIDS. The Mane-A1*084:01 MHC class I allele (previously named Mane-A*10) is important for the control of SIV infection by CD8+ T cells in this model. Validated methods to detect this allele in large numbers of macaques are lacking. We studied this MHC allele using sequence-specific PCRs in 217 pig-tailed macaques and identified 75 (35%) positive animals. We then performed massively parallel pyrosequencing with a universal 568-bp MHC class I cDNA-PCR licon for 50 of these 75 macaques. All 50 animals expressed Mane-A1*084:01 or closely related variants of the Mane-A1*084 lineage. Mane-A1*084 transcripts accounted for an average of 20.9% of all class I sequences identified per animal. SIV infection of a subset of these macaques resulted in the induction of SIV-specific CD8+ T cell responses detected by Mane-A1*084:01 tetramers. An average of 19 distinct class I transcripts were identified per animal by pyrosequencing. This analysis revealed 89 new Mane class I sequences as well as 32 previously described sequences that were extended with the longer licons employed in the current study. In addition, multiple Mane class I haplotypes that had been inferred previously based on shared transcript profiles between unrelated animals were confirmed for a subset of animals where pedigree information was available. We conclude that sequence-specific PCR is useful to screen pig-tailed macaques for Mane-A1*084:01, although pyrosequencing permits a much broader identification of the repertoire of MHC class I sequences and haplotypes expressed by in idual animals.
Modified Vaccinia Virus Ankara Encoding Influenza Virus Hemagglutinin Induces Heterosubtypic Immunity in Macaques
Publisher: American Society for Microbiology
Date: 15-11-2014
DOI: 10.1128/JVI.01219-14
Abstract: Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA-based vaccines 4 weeks apart and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza virus HA and/or NP had high frequencies of virus-specific CD4 + and CD8 + T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC plays a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective. IMPORTANCE Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. Therefore, we evaluated a vaccine strategy designed to induce both antibody and T cell responses, which may provide more broadly cross-protective immunity against influenza. Here, we show in a translational primate model that vaccination with a modified vaccinia virus Ankara encoding hemagglutinin from a heterosubtypic H5N1 virus was associated with reduced shedding of a pandemic H1N1 virus challenge, while vaccination with MVA encoding nucleoprotein, an internal viral protein, was not. Unexpectedly, this reduced shedding was associated with nonneutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Therefore, antibody-dependent cellular cytotoxicity (ADCC) may play a role in cross-protective immunity to influenza virus. Vaccines that stimulate ADCC antibodies may enhance protection against pandemic influenza virus.
Quantitatively Tracking Bio–Nano Interactions of Metal–Phenolic Nanocapsules by Mass Cytometry
Publisher: American Chemical Society (ACS)
Date: 21-07-2021
Minimum information reporting in bio-nano experimental literature
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Antibody-Dependent Cellular Cytotoxicity and NK Cell-Driven Immune Escape in HIV Infection: Implications for HIV Vaccine Development
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/637208
Abstract: The HIV-1 genome is malleable and a difficult target tot vaccinate against. It has long been recognised that cytotoxic T lymphocytes and neutralising antibodies readily select for immune escape HIV variants. It is now also clear that NK cells can also select for immune escape. NK cells force immune escape through both direct Killer-immunoglobulin-like receptor (KIR)-mediated killing as well as through facilitating antibody-dependent cellular cytotoxicity (ADCC). These newer finding suggest NK cells and ADCC responses apply significant pressure to the virus. There is an opportunity to harness these immune responses in the design of more effective HIV vaccines.
Role of monocytes in mediating HIV-specific antibody-dependent cellular cytotoxicity
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.JIM.2012.07.006
Abstract: Antibodies (Abs) that mediate antibody-dependent cellular cytotoxicity (ADCC) activity against HIV-1 are of major interest. A widely used method to measure ADCC Abs is the rapid and fluorometric antibody-dependent cellular cytotoxicity (RFADCC) assay. Antibody-dependent killing of a labelled target cell line by PBMC is assessed by loss of intracellular CFSE but retention of membrane dye PKH26 (CFSE-PKH26+). Cells of this phenotype are assumed to be derived from CFSE+PKH26+ target cells killed by NK cells. We assessed the effector cells that mediate ADCC in this assay. Backgating analysis and phenotyping of CFSE-PKH26+ revealed that the RFADCC assay's readout mainly represents CD3-CD14+ monocytes taking up the PKH26 dye. This was confirmed for 53 HIV+plasma-purified IgG s les when co-cultured with PBMC from three separate healthy donors. Emergence of the CFSE-PKH26+ monocyte population was observed upon co-culture of targets with purified monocytes but not with purified NK cells. Image flow cytometry and microscopy showed a monocyte-specific interaction with target cells without typical morphological changes associated with phagocytosis, suggesting a monocyte-mediated ADCC process. We conclude that the RFADCC assay primarily reflects Ab-mediated monocyte function. Further studies on the immunological importance of HIV-specific monocyte-mediated ADCC are warranted.
CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity
Publisher: Elsevier BV
Date: 05-2021
Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans
Publisher: Elsevier BV
Date: 02-2021
Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells
Publisher: American Society for Microbiology
Date: 15-02-2016
DOI: 10.1128/JVI.02717-15
Abstract: Lifelong antiretroviral therapy (ART) for HIV-1 does not diminish the established latent reservoir. A possible cure approach is to reactivate the quiescent genome from latency and utilize immune responses to eliminate cells harboring reactivated HIV-1. It is not known whether antibodies within HIV-1-infected in iduals can recognize and eliminate cells reactivated from latency through antibody-dependent cellular cytotoxicity (ADCC). We found that reactivation of HIV-1 expression in the latently infected ACH-2 cell line elicited antibody-mediated NK cell activation but did not result in antibody-mediated killing. The lack of CD4 expression on these HIV-1 envelope (Env)-expressing cells likely resulted in poor recognition of CD4-induced antibody epitopes on Env. To examine this further, cultured primary CD4 + T cells from HIV-1 + subjects were used as targets for ADCC. These ex vivo -expanded primary cells were modestly susceptible to ADCC mediated by autologous or heterologous HIV-1 + serum antibodies. Importantly, ADCC mediated against these primary cells could be enhanced following incubation with a CD4-mimetic compound (JP-III-48) that exposes CD4-induced antibody epitopes on Env. Our studies suggest that with sufficient reactivation and expression of appropriate Env epitopes, primary HIV-1-infected cells can be targets for ADCC mediated by autologous serum antibodies and innate effector cells. The results of this study suggest that further investigation into the potential of ADCC to eliminate reactivated latently infected cells is warranted. IMPORTANCE An HIV-1 cure remains elusive due to the persistence of long-lived latently infected cells. An HIV-1 cure strategy, termed “shock and kill,” aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. While recent research efforts have focused on reversing HIV-1 latency, it remains unclear whether preexisting immune responses within HIV-1 + in iduals can efficiently eliminate the reactivated cells. HIV-1-specific antibodies can potentially eliminate cells reactivated from latency via Fc effector functions by recruiting innate immune cells. Our study highlights the potential role that antibody-dependent cellular cytotoxicity might play in antilatency cure approaches.
Thiol-Reactive Star Polymers Display Enhanced Association with Distinct Human Blood Components
Publisher: American Chemical Society (ACS)
Date: 03-04-2017
Abstract: Directing nanoparticles to specific cell types using nonantibody-based methods is of increasing interest. Thiol-reactive nanoparticles can enhance the efficiency of cargo delivery into specific cells through interactions with cell-surface proteins. However, studies to date using this technique have been largely limited to immortalized cell lines or rodents, and the utility of this technology on primary human cells is unknown. Herein, we used RAFT polymerization to prepare pyridyl disulfide (PDS)-functionalized star polymers with a methoxy-poly(ethylene glycol) brush corona and a fluorescently labeled cross-linked core using an arm-first method. PDS star polymers were examined for their interaction with primary human blood components: six separate white blood cell subsets, as well as red blood cells and platelets. Compared with control star polymers, thiol-reactive nanoparticles displayed enhanced association with white blood cells at 37 °C, particularly the phagocytic monocyte, granulocyte, and dendritic cell subsets. Platelets associated with more PDS than control nanoparticles at both 37 °C and on ice, but they were not activated in the duration examined. Association with red blood cells was minor but still enhanced with PDS nanoparticles. Thiol-reactive nanoparticles represent a useful strategy to target primary human immune cell subsets for improved nanoparticle delivery.
Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-08-2230
DOI: 10.1126/SCIIMMUNOL.ABF5314
Abstract: Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (B RM ) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza - specific B RM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)– and nucleoprotein (NP)–specific lung B RM . We found that CCR6 facilitates increased recruitment and/or retention of B RM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning B RM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that B RM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.
A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface
Publisher: Elsevier BV
Date: 05-2019
Immunization with inactivated whole virus particle influenza virus vaccines induces superior immunity in cynomolgus macaques
Publisher: Research Square Platform LLC
Date: 09-03-2022
DOI: 10.21203/RS.3.RS-1390960/V1
Abstract: Influenza viruses circulate globally, causing seasonal influenza outbreaks. Although antibody-inducing vaccines are the most effective way to combat seasonal infections, current vaccines can have poor efficacy, especially in children and immunocompromised in iduals. We investigated the immunogenicity and efficacy of monovalent and quadrivalent formulations of the whole virus particle vaccine (WPV) in comparison to the commonly used split vaccines (SVs) in a non-human primate model. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV formulations consistently induced a stronger neutralizing antibody response against vaccine-matched virus strains, while reactogenicity was minimal. In contrast to the modest responses in SV-vaccinated animals, responses in WPV-primed animals were further increased by boosting with either formulation. Using a 28-parameter multiplex bead array to define key antibody features, we found that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV elevated IgG responses against A/H1N1 haemagglutinin (HA) and HA-Stem after each vaccine dose. Higher IgA responses to A/H1N1-HA were also induced after each WPV dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. WPV-enhanced antibody responses were associated with higher frequencies of HA-reactive B-cells and IFN-γ-producing CD4 + T-cell responses. Our data suggest that robust antibody responses require WPV to be given as a priming dose but do not depend on the vaccine type used for the second dose. In contrast, antibody responses are not as prominent when SV is given first. Our findings support vaccination regimens using WPV, which may be particularly beneficial for priming immunologically-naïve in iduals, such as the young and immunocompromised, and also advantageous in the event of a pandemic outbreak.
Innate and Adaptive Anti-SIV Responses in Macaque Semen: Implications for Infectivity and Risk of Transmission.
Publisher: Frontiers Media SA
Date: 12-05-2020
Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41467-021-23018-X
Abstract: How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal s les from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8 + or CD4 + T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
Modeling the Timing of Antilatency Drug Administration during HIV Treatment
Publisher: American Society for Microbiology
Date: 15-12-2014
DOI: 10.1128/JVI.01701-14
Abstract: Latently infected cells are considered a major barrier to the cure of HIV infection, since they are long-lived under antiretroviral therapy (ART) and cause viral replication to restart soon after stopping ART. In the last decade, different types of antilatency drugs have been explored with the aim of reactivating and purging this latent reservoir and the hope of achieving a cure. Because of toxicity and safety considerations, antilatency drugs can only be given for a short time to patients on long-term ART, with little effect. We recently investigated the turnover of latently infected cells during active infection and have found that it was strongly correlated with viral load. This implies that although latently infected cells had long life spans in a setting of a low viral load (such as during ART), they turned over quickly under a high viral load. Possible reasons for this could be that an increased viral load causes increased activation or death of CD4 + T cells, including those that are latently infected. Taking these results into account, we developed a mathematical model to study the most appropriate timing of antilatency drugs in relationship to the initiation of ART. We found that the best timing of a short-term antilatency drug would be the start of ART, when viral load, CD4 + T cell activation, and latent cell turnover are all high. These results have important implications for the design of HIV cure-related clinical trials. IMPORTANCE The antiretroviral therapy (ART) of HIV-infected patients currently needs to be lifelong, because the cells latently infected with HIV start new rounds of infection as soon as the treatment is stopped. In the last decade, a number of different types of antilatency drugs have been explored with the aim of “reactivating” and “purging” this latent reservoir and thus achieving a cure. These drugs have thus far been tested on patients only after long-term ART and have demonstrated little or no effect. We use mathematical modeling to show that the most efficacious timing of a short-term antilatency treatment may be the start of ART because of possible interactions of antilatency drugs with natural activation pathways.
Cross-lineage protection by human antibodies binding the influenza B hemagglutinin
Publisher: Springer Science and Business Media LLC
Date: 18-01-2019
DOI: 10.1038/S41467-018-08165-Y
Abstract: Influenza B viruses (IBV) drive a significant proportion of influenza-related hospitalisations yet are understudied compared to influenza A. Current vaccines target the head of the viral hemagglutinin (HA) which undergoes rapid mutation, significantly reducing vaccine effectiveness. Improved vaccines to control IBV are needed. Here we developed novel IBV HA probes to interrogate humoral responses to IBV in humans. A significant proportion of IBV HA-specific B cells recognise both B/Victoria/2/87-like and B/Yamagata/16/88-like lineages in a distinct pattern of cross-reactivity. Monoclonal antibodies (mAbs) were reconstituted from IBV HA-specific B cells, including mAbs providing broad protection in murine models of lethal IBV infection. Protection was mediated by neutralising antibodies targeting the receptor binding domain, or via Fc-mediated functions of non-neutralising antibodies binding alternative epitopes including the IBV HA stem. This work defines antigenic cross-recognition between IBV lineages and provides guidance for the rational design of improved IBV vaccines for broad and durable protection.
SARS-CoV-2 variants: levels of neutralisation required for protective immunity
Publisher: Cold Spring Harbor Laboratory
Date: 13-08-2021
DOI: 10.1101/2021.08.11.21261876
Abstract: A number of SARS-CoV-2 variants of concern (VOC) have been identified that partially escape serum neutralisation activity elicited by current vaccines. Recent studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. Here we integrate published data on in vitro neutralisation and clinical protection to understand and predict vaccine efficacy against existing SARS-CoV-2 variants. We find that neutralising activity against the ancestral SARS-CoV-2 is highly predictive of neutralisation of the VOC, with all vaccines showing a similar drop in neutralisation to the variants. Neutralisation levels remain strongly correlated with protection from infection with SARS-CoV-2 VOC (r=0.81, p=0.0005). We apply an existing model relating in vitro neutralisation to protection (parameterised on data from ancestral virus infection) and find this remains predictive of vaccine efficacy against VOC once drops in neutralisation to the VOC are taken into account. Modelling of predicted vaccine efficacy against variants over time suggests that protection against symptomatic infection may drop below 50% within the first year after vaccination for some current vaccines. Boosting of previously infected in iduals with existing vaccines (which target ancestral virus) has been shown to significantly increase neutralising antibodies. Our modelling suggests that booster vaccination should enable high levels of immunity that prevent severe infection outcomes with the current SARS-CoV-2 VOC, at least in the medium term.
Induction of SerpinB2 and Th1/Th2 modulation by SerpinB2 during lentiviral infections in vivo.
Publisher: Public Library of Science (PLoS)
Date: 27-02-2013
Balancing Reversion of Cytotoxic T-Lymphocyte and Neutralizing Antibody Escape Mutations within Human Immunodeficiency Virus Type 1 Env upon Transmission
Publisher: American Society for Microbiology
Date: 09-2009
DOI: 10.1128/JVI.00599-09
Abstract: Human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) is subject to both neutralizing antibody (NAb) and CD8 T-cell (cytotoxic T-lymphocyte [CTL]) immune pressure. We studied the reversion of the Env CTL escape mutant virus to the wild type and the relationship between the reversion of CTL mutations with N-linked glycosylation site (NLGS)-driven NAb escape in pigtailed macaques. Env CTL mutations either did not revert to the wild type or only transiently reverted 5 to 7 weeks after infection. The CTL escape mutant reversion was coincident, for the same viral clones, with the loss of NLGS mutations. At one site studied, both CTL and NLGS mutations were needed to confer NAb escape. We conclude that CTL and NAb escape within Env can be tightly linked, suggesting opportunities to induce effective multicomponent anti-Env immunity.
Attenuated and wild-type HIV-1 infections and long terminal repeat-mediated gene expression from plasmids delivered by gene gun to human skin ex vivo and macaques in vivo
Publisher: Elsevier BV
Date: 08-2001
Tuning the properties of pH responsive nanoparticles to control cellular interactions in vitro and ex vivo
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6PY01332E
Abstract: Engineering the properties of nanoparticles to limit non-specific cellular interactions is critical for developing effective drug delivery systems. Differences between interactions with cultured cells and human blood highlights the need for appropriate assays.
Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1424
Abstract: Following infection with SARS‐CoV‐2, virus‐specific antibodies are generated, which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS‐CoV‐2 has been extensively reported. By comparison, other antibody isotypes including IgA have been poorly characterised. Here, we characterised plasma IgA from 41 early convalescent COVID‐19 subjects for neutralisation and Fc effector functions. Convalescent plasma IgA from 60% of the cohort had the capacity to inhibit the interaction between wild‐type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA‐mediated ACE2 inhibition than matched IgG when tested at equivalent concentrations. Plasma IgA and IgG from this cohort broadly recognised similar RBD epitopes and had similar capacities to inhibit ACE2 from binding to 22 of the 23 prevalent RBD mutations assessed. However, plasma IgA was largely incapable of mediating antibody‐dependent phagocytosis in comparison with plasma IgG. Overall, convalescent plasma IgA contributed to the neutralising antibody response of wild‐type SARS‐CoV‐2 RBD and various RBD mutations. However, this response displayed large heterogeneity and was less potent than IgG.
Serum IgA Fc effector functions in infectious disease and cancer
Publisher: Wiley
Date: 05-03-0001
DOI: 10.1111/IMCB.12306
CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection
Publisher: MDPI AG
Date: 18-01-2021
DOI: 10.3390/IJMS22020912
Abstract: HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4% p = 0.002) and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3% p 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.
Preventive HIV-1 vaccines: where are we going?
Publisher: SAGE Publications
Date: 12-1998
Link between Low-Fouling and Stealth: A Whole Blood Biomolecular Corona and Cellular Association Analysis on Nanoengineered Particles.
Publisher: American Chemical Society (ACS)
Date: 18-04-2019
Abstract: Upon exposure to human blood, nanoengineered particles interact with a multitude of plasma components, resulting in the formation of a biomolecular corona. This corona modulates downstream biological responses, including recognition by and association with human immune cells. Considerable research effort has been directed toward the design of materials that can demonstrate a low affinity for various proteins (low-fouling materials) and materials that can exhibit low association with human immune cells (stealth materials). An implicit assumption common to bio-nano research is that nanoengineered particles that are low-fouling will also exhibit stealth. Herein, we investigated the link between the low-fouling properties of a particle and its propensity for stealth in whole human blood. High-fouling mesoporous silica (MS) particles and low-fouling zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) particles were synthesized, and their interaction with blood components was assessed before and after precoating with serum albumin, immunoglobulin G, or complement protein C1q. We performed an in-depth proteomics characterization of the biomolecular corona that both identifies specific proteins and measures their relative abundance. This was compared with observations from a whole blood association assay that identified with which cell type each particle system associates. PMPC-based particles displayed reduced association both with cells and with serum proteins compared with MS-based particles. Furthermore, the enrichment of specific proteins within the biomolecular corona was found to correlate with association with specific cell types. This study demonstrates how the low-fouling properties of a material are indicative of its stealth with respect to immune cell association.
Landscape of human antibody recognition of the SARS-CoV-2 receptor binding domain
Publisher: Elsevier BV
Date: 10-2021
Enhanced cellular immunity in macaques following a novel peptide immunotherapy
Publisher: American Society for Microbiology
Date: 15-03-2005
DOI: 10.1128/JVI.79.6.3748-3757.2005
Abstract: Advances in treating and preventing AIDS depend on understanding how human immunodeficiency virus (HIV) is eliminated in vivo and on the manipulation of effective immune responses to HIV. During the development of assays quantifying the elimination of fluorescent autologous cells coated with overlapping 15-mer simian immunodeficiency virus (SIV) or HIV-1 peptides, we made a remarkable observation: the reinfusion of macaque peripheral blood mononuclear cells, or even whole blood, pulsed with SIV and/or HIV peptides generated sharply enhanced SIV- and HIV-1-specific T-cell immunity. Strong, broad CD4 + - and CD8 + -T-cell responses could be enhanced simultaneously against peptide pools spanning 87% of all SIV- and HIV-1-expressed proteins—highly desirable characteristics of HIV-specific immunity. De novo hepatitis C virus-specific CD4 + - and CD8 + -T-cell responses were generated in macaques by the same method. This simple technique holds promise for the immunotherapy of HIV and other chronic viral infections.
HIV-specific antibody-dependent phagocytosis matures during HIV infection
Publisher: Wiley
Date: 10-06-2014
DOI: 10.1038/ICB.2014.42
Abstract: Antibody-dependent phagocytosis (ADP) is a potentially important immune mechanism to clear HIV. How HIV-specific ADP responses mature during HIV infection or in response to vaccinations administered, including the partially successful RV144 HIV vaccine, is not known. We established a modified ADP assay to measure internalisation of HIV antibody (Ab)-opsonised targets using a specific hybridisation internalisation probe. Labelled beads were coated with both biotinylated HIV gp140 envelope protein and a fluorescent internalisation probe, opsonised with Abs and incubated with a monocytic cell line. The fluorescence derived from the fluorescent internalisation probe on surface-bound beads, but not from internalised beads, was quenched by the addition of a complementary quencher probe. HIV Env-specific ADP was measured in 31 subjects during primary infection and early chronic HIV infection. Although ADP responses were present early during HIV infection, a significant increase in ADP responses in all 31 subjects studied was detected (P<0.001). However, when we tested 30 HIV-negative human subjects immunised with the Canarypox/gp120 vaccine regimen (subjects from the RV144 trial) we did not detect HIV-specific ADP activity. In conclusion, a modified assay was developed to measure HIV-specific ADP. Enhanced ADP responses early in the course of HIV infection were observed but no ADP activity was detected following the vaccinations administered in the RV144 trial. Improved vaccine regimens may be needed to capitalise on ADP-mediated immunity against HIV.
Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
Fitness Constraints on Immune Escape from HIV: Implications of Envelope as a Target for Both HIV-Specific T Cells and Antibody
Publisher: Bentham Science Publishers Ltd.
Date: 04-2006
DOI: 10.2174/157016206776055110
Abstract: Sterilising immunity against HIV-1 infection, whilst ideal, appears an unrealistic vaccination goal in the short term. More achievable is slowing the progression to disease and decreasing transmission by mounting strong T cell and neutralising antibody responses to maintain low viral loads. However, in both acute and chronic infection, mutant virus is selected to escape both arms of the adaptive immune system. Each mutation away from wildtype virus likely incurs at least some reduction in replicative capacity ("fitness") of the virus. Rapid reversion to wildtype of some immune escape mutations upon transmission, suggests fitness costs may be significant. HIV-1 Envelope is unique in that it is subject to both neutralising antibody and cell-mediated immune responses. Although Envelope is variable between strains, considerable serial pressure and mutational escape from both neutralising antibody and cytotoxic T lymphocyte attack may result in impaired structure and function. This could ultimately be exploited in HIV vaccine design.
HIV vaccines moving forward
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2016
Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies
Publisher: Wiley
Date: 14-03-2019
Abstract: Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs-one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)-is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.
HIV Reactivation from Latency after Treatment Interruption Occurs on Average Every 5-8 Days—Implications for HIV Remission
Publisher: Public Library of Science (PLoS)
Date: 02-07-2015
The primary immune response to Vaccinia virus vaccination includes cells with a distinct cytotoxic effector CD4 T-cell phenotype
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.VACCINE.2016.09.009
Abstract: Smallpox was eradicated by a global program of inoculation with Vaccinia virus (VV). Robust VV-specific CD4 T-cell responses during primary infection are likely essential to controlling VV replication. Although there is increasing interest in cytolytic CD4 T-cells across many viral infections, the importance of these cells during acute VV infection is unclear. We undertook a detailed functional and genetic characterization of CD4 T-cells during acute VV-infection of humans. VV-specific T-cells were identified by up-regulation of activation markers directly ex vivo and through cytokine and co-stimulatory molecule expression. At day-13-post primary inoculation with VV, CD38highCD45RO+ CD4 T-cells were purified by cell sorting, RNA isolated and analysed by microarray. Differential expression of up-regulated genes in activated CD4 T-cells was confirmed at the mRNA and protein levels. We compared analyses of VV-specific CD4 T-cells to studies on 12 subjects with primary HIV infection (PHI). VV-specific T-cells lines were established from PBMCs collected post vaccination and checked for cytotoxicity potential. A median 11.9% CD4 T-cells were CD38highCD45RO+ at day-13 post-VV inoculation, compared to 3.0% prior and 10.4% during PHI. Activated CD4 T-cells had an up-regulation of genes related to cytolytic function, including granzymes K and A, perforin, granulysin, TIA-1, and Rab27a. No difference was seen between CD4 T-cell expression of perforin or TIA-1 to VV and PHI, however granzyme k was more dominant in the VV response. At 25:1 effector to target ratio, two VV-specific T-cell lines exhibited 62% and 30% cytotoxicity respectively and CD107a degranulation. We show for the first time that CD4 CTL are prominent in the early response to VV. Understanding the role of CD4 CTL in the generation of an effective anti-viral memory may help develop more effective vaccines for diseases such as HIV.
Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein
Publisher: Elsevier BV
Date: 09-2021
Chimeric human papilloma virus-simian/human immunodeficiency virus virus-like-particle vaccines: Immunogenicity and protective efficacy in macaques
Publisher: Elsevier BV
Date: 09-2002
Abstract: Vaccines to efficiently block or limit sexual transmission of both HIV and human papilloma virus (HPV) are urgently needed. Chimeric virus-like-particle (VLP) vaccines consisting of both multimerized HPV L1 proteins and fragments of SIV gag p27, HIV-1 tat, and HIV-1 rev proteins (HPV-SHIV VLPs) were constructed and administered to macaques both systemically and mucosally. An additional group of macaques first received a priming vaccination with DNA vaccines expressing the same SIV and HIV-1 antigens prior to chimeric HPV-SHIV VLP boosting vaccinations. Although HPV L1 antibodies were induced in all immunized macaques, weak antibody or T cell responses to the chimeric SHIV antigens were detected only in animals receiving the DNA prime/HPV-SHIV VLP boost vaccine regimen. Significant but partial protection from a virulent mucosal SHIV challenge was also detected only in the prime/boosted macaques and not in animals receiving the HPV-SHIV VLP vaccines alone, with three of five prime/boosted animals retaining some CD4+ T cells following challenge. Thus, although some immunogenicity and partial protection was observed in non-human primates receiving both DNA and chimeric HPV-SHIV VLP vaccines, significant improvements in vaccine design are required before we can confidently proceed with this approach to clinical trials.
Can HIV Infection be Prevented with a Vaccine?
Publisher: Springer Science and Business Media LLC
Date: 1999
DOI: 10.2165/00126839-199901060-00001
Abstract: The global human immunodeficiency virus type 1 (HIV-1) epidemic is devastating many communities and a well tolerated and effective vaccine is urgently required. Several lines of evident suggest that vaccine-induced protective immunity can be achieved. This evidence includes in iduals shown to have natural immunity, and the partially effective immune responses that are generated during natural infection. However, the obstacles to HIV-1 vaccine development are enormous. The only substantially effective vaccine studied in pathogenic animal models (live, attenuated vaccines) is at present far too unsafe. The only HIV-1 vaccine to proceed to efficacy trials (an envelope protein approach) has been disappointing in its immunogenicity and efficacy in preliminary trials. The antigenic variability of HIV-1 strains is also a great obstacle. Unfortunately, commercial realities also do not favour the expensive development of HIV-1 vaccines required most urgently in less developed countries. Despite these obstacles, there is cause for cautious optimism. Better tolerated HIV-1 vaccine approaches are currently showing great promise in primate models and preliminary clinical trials. Many governments and the World Bank are now providing the political will and funding necessary to fast-track HIV-1 vaccine development. Given sufficient long term scientific and commercial commitment to the HIV-1 vaccine development process, it is ultimately likely that a preventative HIV-1 vaccine will emerge.
The search for an HIV cure: tackling latent infection
Publisher: Elsevier BV
Date: 07-2013
In Vivo Fitness Costs of Different Gag CD8 T-Cell Escape Mutant Simian-Human Immunodeficiency Viruses for Macaques
Publisher: American Society for Microbiology
Date: 15-05-2007
DOI: 10.1128/JVI.02763-06
Abstract: The kinetics of immune escape and reversion depend upon the efficiency of CD8 cytotoxic T lymphocytes (CTL) and the fitness cost of escape mutations. Escape kinetics of three simian immunodeficiency virus Gag CTL epitopes in pigtail macaques were variable those of KP9 and AF9 were faster than those of KW9. Kinetics of reversion of escape mutant virus to wild type upon passage to naïve major histocompatibility complex-mismatched macaques also varied. Rapid reversion occurred at KP9, gradual biphasic reversion occurred at AF9, and escape mutant KW9 virus failed to revert. The fitness impact of these mutations is KP9 AF9 KW9. These data provide insights into the differential utility of CTL in controlling viremia.
A Lipid/DNA Adjuvant–Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge
Publisher: Oxford University Press (OUP)
Date: 26-04-2018
Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection
Publisher: Cold Spring Harbor Laboratory
Date: 06-06-2022
DOI: 10.1101/2022.06.05.22275943
Abstract: Several studies show neutralizing antibody levels are an important correlate of immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, a number of these studies appear to yield quite different estimates of the level of neutralizing antibodies required for protection. Here we show that after normalization of antibody titers current studies converge on a consistent relationship between antibody levels and protection from COVID-19.
Standard Trivalent Influenza Virus Protein Vaccination Does Not Prime Antibody-Dependent Cellular Cytotoxicity in Macaques
Publisher: American Society for Microbiology
Date: 15-12-2013
DOI: 10.1128/JVI.01666-13
Abstract: Yearly vaccination with the trivalent inactivated influenza vaccine (TIV) is recommended, since current vaccines induce little cross neutralization to ergent influenza strains. Whether the TIV can induce antibody-dependent cellular cytotoxicity (ADCC) responses that can cross-recognize ergent influenza virus strains is unknown. We immunized 6 influenza-naive pigtail macaques twice with the 2011–2012 season TIV and then challenged the macaques, along with 12 control macaques, serially with H1N1 and H3N2 viruses. We measured ADCC responses in plasma to a panel of H1 and H3 hemagglutinin (HA) proteins and influenza virus-specific CD8 T cell (CTL) responses using a sensitive major histocompatibility complex (MHC) tetramer reagent. The TIV was weakly immunogenic and, although binding antibodies were detected by enzyme-linked immunosorbent assay (ELISA), did not induce detectable influenza virus-specific ADCC or CTL responses. The H1N1 challenge elicited robust ADCC to both homologous and heterologous H1 HA proteins, but not influenza virus HA proteins from different subtypes (H2 to H7). There was no anamnestic influenza virus-specific ADCC or CTL response in vaccinated animals. The subsequent H3N2 challenge did not induce or boost ADCC either to H1 HA proteins or to ergent H3 proteins but did boost CTL responses. ADCC or CTL responses were not induced by TIV vaccination in influenza-naive macaques. There was a marked difference in the ability of infection compared to that of vaccination to induce cross-reactive ADCC and CTL responses. Improved vaccination strategies are needed to induce broad-based ADCC immunity to influenza.
Obstacles to ideal anti-HIV antibody-dependent cellular cytotoxicity responses
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.VACCINE.2013.08.035
Abstract: A safe and effective vaccine against HIV is a global health priority. Large-scale phase III clinical vaccine trials based on neutralizing antibodies and cytotoxic T-lymphocytes have failed to provide protection, highlighting the lack of understanding of basic immune correlates of protection against HIV. The partial success of the RV144 vaccine trial, however, sparked an intense research effort to identify and describe the protective potential of non-neutralizing antibodies. Correlates of protection analyses have identified antibodies that induced antibody-dependent cellular cytotoxicity (ADCC) as potentially important. Despite the attractiveness of utilizing ADCC antibodies for HIV vaccine design, it is important to note that effective ADCC responses are contingent on many factors. As discussed in this review, these factors are important considerations for determining the feasibility of designing an optimal ADCC antibody-inducing vaccine construct. Important determinants of ADCC responses include characteristics of the antibody, such as isotype and subclass, antigen-specificity, titer, durability and glycosylation of the constant region. Second, ADCC immune responses are highly contingent on the natural killer (NK) cell effectors. This review will describe the current state of knowledge regarding the ontogeny of NK cells, highlighting the continuous "education" they undergo that determines their functional potential upon stimulation. Other important NK cell factors, such as constant region receptor polymorphisms, cellular exhaustion, and the effects of the cytokine milieu on cellular function, will also be covered. Finally, an exciting, but yet untested, role for NK cell-mediated ADCC lies in its potential ability to eliminate latently infected cells, which harbor the viral reservoir. The review will address the potential of a two-pronged attack, where latently infected cells are induced to express HIV antigens and then eliminated by NK cells via an ADCC mechanism, with the goal of inducing a cure.
Simian immunodeficiency virus infection and immune responses in the pig-tailed macaque testis
Publisher: Oxford University Press (OUP)
Date: 20-01-2015
Abstract: The testis is a site of immune privilege in rodents, and there is evidence that T cell responses are also suppressed in the primate testis. Local immunosuppression is a potential mechanism for HIV persistence in tissue reservoirs that few studies have examined. The response of the pig-tailed macaque testis to SIVmac239 infection was characterized to test this possibility. Testes were surgically removed during early-chronic (10 wk) and late-chronic (24–30 wk) SIV infection in 4 animals and compared with those from 7 uninfected animals. SIV infection caused only minor disruption to the seminiferous epithelium without marked evidence of inflammation or consistent changes in total intratesticular leukocyte numbers. Infection also led to an increase in the relative proportion of testicular effector memory CD8+ T cell numbers and a corresponding reduction in central memory CD4+ T cells. A decrease in the relative proportion of resident-type CD163+ macrophages and DCs was also observed. SIV-specific CD8+ T cells were detectable in the testis, 10–11 wk after infection by staining with SIV Gag-specific or Tat-specific MHC-I tetramers. However, testicular CD8+ T cells from the infected animals had suppressed cytokine responses to mitogen activation. These results support the possibility that local immunosuppression in the testis may be restricting the ability of T cells to respond to SIV or HIV infection. Local immunosuppression in the testis may be an underexplored mechanism allowing HIV persistence.
Robust immunity to influenza vaccination in haematopoietic stem cell transplant recipients following reconstitution of humoral and adaptive immunity
Publisher: Wiley
Date: 2023
DOI: 10.1002/CTI2.1456
Abstract: Influenza causes significant morbidity and mortality, especially in high‐risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high‐risk groups, such as haematopoietic stem cell transplant (HSCT) recipients. We comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza‐specific B‐cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls. Inactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class‐switched and CD21 lo CD27 + influenza‐specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross‐reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre‐existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second‐dose patients reached a seroprotective HAI titre for at least one of vaccine strains. Our study demonstrates efficient, although time‐dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high‐risk groups.
Comparison of whole gene and whole virus scrambled antigen approaches for DNA prime and fowlpox virus boost HIV type 1 vaccine regimens in macaques
Publisher: Mary Ann Liebert Inc
Date: 04-2005
Abstract: T cell immunity plays a critical role in controlling HIV-1 viremia, and encoding a limited set of HIV-1 genes within DNA and poxvirus vectors can, when used sequentially, induce high levels of T cell immunity in primates. However, a limited breadth of T cell immunity exposes the host to potential infection with either genetically erse HIV-1 strains or T cell escape variants of HIV-1. In an attempt to induce maximally broad immunity, we examined DNA and recombinant fowlpox virus (rFPV) vaccines encoding all HIV-1 genes derived from a global HIV-1 consensus sequence, but expressed as multiple overlapping scrambled 30-amino acid segments (scrambled antigen vaccines, or SAVINEs). Three groups of seven pigtail macaques were immunized with sets of DNA and rFPV expressing Gag/Pol antigens only, the whole genome SAVINE antigens, or no HIV-1 antigens and T cell immunity was monitored by ELISpot and intracellular cytokine staining. High levels of cross-subtype HIV-specific T cell immunity to Gag were consistently induced in the seven macaques primed with DNA and rFPV vaccines expressing Gag/Pol as intact proteins. It was, however, difficult to repeatedly boost immunity with further rFPV immunizations, presumably reflecting high levels of anti- FPV immunity. Unfortunately, this vaccine study did not consistently achieve a broadened level of T cell immunity to multiple HIV genes utilizing the novel whole-virus SAVINE approach, with only one of seven immunized animals generating broad T cell immunity to multiple HIV-1 proteins. Further refinements are planned with alternative vector strategies to evaluate the potential of the SAVINE technology.
Ex-vivo α-Galactosylceramide activation of NKT cells in humans and macaques
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.JIM.2012.05.019
Abstract: NKT cells are key mediators of antiviral and anticancer immunity. Experiments in mice have demonstrated that activation of NKT cells in vivo induces the expression of multiple effector molecules critical to successful immunity. Human clinical trials have shown similar responses, although in vivo activation of NKT cells in humans or primate models are far more limited in number and scope. Measuring ex vivo activation of NKT cells by the CD1d-restricted glycolipid ligand α-Galactosylceramide (α-GalCer) through cytokine expression profiles is a useful marker of NKT cell function, but for reasons that are unclear, this approach does not appear to work as well in humans and non-human primate macaque models in comparison to mice. We performed a series of experiments on human and macaque (Macaca nemestrina) fresh whole blood s les to define optimal conditions to detect NKT cell cytokine (TNF, IFNγ, IL-2) and degranulation marker (CD107a) expression by flow cytometry. We found that conditions previously described for mouse splenocyte NKT cell activation were suboptimal on human or macaque blood NKT cells. In contrast, a 6h incubation with brefeldin A added for the last 4h, in a 96-well plate based assay, and using an α-GalCer concentration of 1 μg/ml were optimal methods to stimulate NKT cells in fresh blood from both humans and macaques. Unexpectedly, we noted that blood NKT cells from macaques infected with SIV were more readily activated by α-GalCer than NKT cells from uninfected macaques, suggesting that SIV infection may have primed the NKT cells. In conclusion, we describe optimized methods for the ex vivo antigen-specific activation of human and macaque blood NKT cells. These assays should be useful in monitoring NKT cells in disease and in immunotherapy studies.
Fc or not Fc; that is the question: Antibody Fc-receptor interactions are key to universal influenza vaccine design
Publisher: Informa UK Limited
Date: 03-04-2017
2017 international meeting of the Global Virus Network.
Publisher: Elsevier BV
Date: 05-2018
Two Families of Env Antibodies Efficiently Engage Fc-Gamma Receptors and Eliminate HIV -1-Infected Cells
Publisher: American Society for Microbiology
Date: 02-2019
DOI: 10.1128/JVI.01823-18
Abstract: The “open” CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV-positive (HIV + ) sera, such as anti-coreceptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcγRIIIa and mediate ADCC.
Trying to cure HIV with immunotherapy: not so simple
Publisher: Elsevier BV
Date: 03-2015
Low pre-infection levels and loss of central memory CD4+ T cells may predict rapid progression in SIV-infected pigtail macaques
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.VIROL.2008.08.042
Abstract: CD4+ T lymphocyte subsets are targeted to different degrees by SIV infection. We studied central memory, effector memory, naïve, and regulatory T cell levels longitudinally in 11 SIV(mac251)-infected pigtail macaques. Depletion of CD28+CD95+ central memory CD4+ T cells, but not other populations, correlated with both SIV viral load and disease progression. A low pre-infection level of central memory CD4+ T cells was also predictive of rapid disease progression. If confirmed in larger studies, our results suggest stratifying macaques for baseline central memory CD4+ T cells would be useful in defining both the pathogenesis of SIV disease and SIV vaccine efficacy.
Stealth nanorods via the aqueous living crystallisation-driven self-assembly of poly(2-oxazoline)s
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1SC00938A
Abstract: Triggered by heating, a poly(2-alkyl-2-oxazoline) block copolymer undergoes seeded growth in water forming length tuneable nanorods. Morphology and composition combine to impart low immune cell association and promising blood circulation lifetimes.
Cutting Edge: SARS-CoV-2 Infection Induces Robust Germinal Center Activity in the Human Tonsil
Publisher: The American Association of Immunologists
Date: 15-05-2022
Abstract: Understanding the generation of immunity to SARS-CoV-2 in lymphoid tissues draining the site of infection has implications for immunity to SARS-CoV-2. We performed tonsil biopsies under local anesthesia in 19 subjects who had recovered from SARS-CoV-2 infection 24–225 d previously. The biopsies yielded & million cells for flow cytometric analysis in 17 subjects. Total and SARS-CoV-2 spike-specific germinal center B cells, and T follicular helper cells, were readily detectable in human tonsils early after SARS-CoV-2 infection, as assessed by flow cytometry. Responses were higher in s les within 2 mo of infection but still detectable in some subjects out to 7 mo following infection. We conclude the tonsils are a secondary lymphoid organ that develop germinal center responses to SARS-CoV-2 infection and could play a role in the long-term development of immunity.
Functional cure of HIV: the scale of the challenge
Publisher: Springer Science and Business Media LLC
Date: 08-11-2019
DOI: 10.1038/S41577-018-0085-4
Abstract: A variety of interventions to induce a functional cure of HIV are being explored, with the aim being to allow patients to cease antiretroviral therapy (ART) for prolonged periods of time or for life. These interventions share the goal of inducing ART-free remission from HIV pathogenesis and disease progression but achieve this in quite different ways, by reducing the size of the latent reservoir (for ex le, small-molecule stimulation of latently infected cells), reducing the number of target cells available for the virus (for ex le, gene therapy) or improving immune responses (for ex le, active or passive immunotherapy). Here, we consider a number of these alternative strategies for inducing post-treatment control of HIV and use mathematical modelling to predict the scale of the challenge inherent in these different approaches. For many approaches, over 99.9% efficacy will likely be required to induce durable ART-free remissions. The efficacy of in idual approaches is currently far below what we predict will be necessary, and new technologies to achieve lifelong functional cure are needed.
Immune imprinting and SARS-CoV-2 vaccine design
Publisher: Elsevier BV
Date: 11-2021
Human immune cell targeting of protein nanoparticles-caveospheres
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6NR00506C
Abstract: Nanotechnology has the power to transform vaccine and drug delivery through protection of payloads from both metabolism and off-target effects, while facilitating specific delivery of cargo to immune cells. However, evaluation of immune cell nanoparticle targeting is conventionally restricted to monocultured cell line models. We generated human caveolin-1 nanoparticles, termed caveospheres, which were efficiently functionalized with monoclonal antibodies. Using this platform, we investigated CD4+ T cell and CD20+ B cell targeting within physiological mixtures of primary human blood immune cells using flow cytometry, imaging flow cytometry and confocal microscopy. Antibody-functionalization enhanced caveosphere binding to targeted immune cells (6.6 to 43.9-fold) within mixed populations and in the presence of protein-containing fluids. Moreover, targeting caveospheres to CCR5 enabled caveosphere internalization by non-phagocytic CD4+ T cells--an important therapeutic target for HIV treatment. This efficient and flexible system of immune cell-targeted caveosphere nanoparticles holds promise for the development of advanced immunotherapeutics and vaccines.
Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models
Publisher: Springer Science and Business Media LLC
Date: 02-11-2020
Vaccine-induced T cells control reversion of AIDS virus immune escape mutants
Publisher: American Society for Microbiology
Date: 15-04-2007
DOI: 10.1128/JVI.02193-06
Abstract: Many current-generation human immunodeficiency virus (HIV) vaccines induce specific T cells to control acute viremia, but their utility following infection with escape mutant virus is unclear. We studied reversion to wild type of an escape mutant simian-HIV in major histocompatibility complex-matched vaccinated pigtail macaques. High levels of vaccine-induced CD8 + T cells strongly correlated with maintenance of escape mutant virus during acute infection. Interestingly, in animals with lower CD8 + T-cell levels, transient reversion to wild-type virus resulted in better postacute control of viremia. Killing of wild-type virus facilitated by transient reversion outweighs the benefit of a larger CD8 + T-cell response that only maintains the less fit escape mutant virus. These findings have important implications for the further development of T-cell-based HIV vaccines where exposure to escape mutant viruses is common.
Does Cytolysis by CD8+ T Cells Drive Immune Escape in HIV Infection?
Publisher: The American Association of Immunologists
Date: 11-2010
Abstract: CD8+ “cytotoxic” T cells are important for the immune control of HIV and the closely related simian models SIV and chimeric simian–human immunodeficiency virus (SHIV), although the mechanisms of this control are unclear. One effect of CD8+ T cell-mediated recognition of virus-infected cells is the rapid selection of escape mutant (EM) virus that is not recognized. To investigate the mechanisms of virus-specific CD8+ T cell control during immune escape in vivo, we used a real-time PCR assay to study the dynamics of immune escape in early SHIV infection of pigtail macaques. For immune escape mediated by cytolysis, we would expect that the death rate of wild type (WT) infected cells should be faster than that of EM-infected cells. In addition, escape should be fastest during periods when the total viral load is declining. However, we find that there is no significant difference in the rate of decay of WT virus compared with EM virus. Further, immune escape is often fastest during periods of viral growth, rather than viral decline. These dynamics are consistent with an epitope-specific, MHC class I-restricted, noncytolytic mechanism of CD8+ T cell control of SHIV that specifically inhibits the growth of WT virus in vivo.
Monoclonal antibodies against human coronavirus NL63 spike
Publisher: Cold Spring Harbor Laboratory
Date: 13-03-2023
DOI: 10.1101/2023.03.12.532265
Abstract: The COVID-19 pandemic has illustrated the potential for monoclonal antibody therapeutics as prophylactic and therapeutic agents against pandemic viruses. No such therapeutics currently exist for other human coronaviruses. NL63 is a human alphacoronavirus that typically causes the common cold and uses the same receptor, ACE2, as the highly pathogenic SARS-CoV and SARS-CoV-2 pandemic viruses. In a cohort of healthy adults, we characterised humoral responses against the NL63 spike protein. While NL63 spike and receptor binding domain-specific binding antibodies and neutralisation activity could be detected in plasma of all subjects, memory B cells against NL63 spike were variable and relatively low in frequency compared to that against SARS-CoV-2 spike. From these donors, we isolated a panel of antibodies against NL63 spike and characterised their neutralising potential. We identified potent neutralising antibodies that recognised the receptor binding domain (RBD) and other non-RBD epitopes within spike.
MHC class I allele frequencies in pigtail macaques of diverse origin.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2006
DOI: 10.1007/S00251-006-0164-8
Abstract: Pigtail macaques (Macaca nemestrina) are an increasingly common primate model for the study of human AIDS. Major Histocompatibility complex (MHC) class I-restricted CD8(+) T cell responses are a critical part of the adaptive immune response to HIV-1 in humans and simian immunodeficiency virus (SIV) in macaques however, MHC class I alleles have not yet been comprehensively characterized in pigtail macaques. The frequencies of ten previously defined alleles (four Mane-A and six Mane-B) were investigated in detail in 109 pigtail macaques using reference strand-mediated conformational analysis (RSCA). The macaques were derived from three separate breeding colonies in the USA, Indonesia and Australia, and allele frequencies were analysed within and between these groups. Mane-A*10, an allele that restricts the immunodominant SIV Gag epitope KP9, was the most common allele, present in 32.1% of the animals overall, with similar frequencies across the three cohorts. Additionally, RSCA identified a new allele (Mane-A*17) common to three Indonesian pigtail macaques responding to the same Gag CD8(+) T cell epitope. This broad characterization of common MHC class I alleles in more than 100 pigtail macaques further develops this animal model for the study of virus-specific CD8(+) T cell responses.
HIV-Specific Antibody Immunity Mediated Through NK Cells and Monocytes
Publisher: Bentham Science Publishers Ltd.
Date: 11-2013
DOI: 10.2174/1570162X113116660061
Abstract: The partial success of the RV144 trial re-energized the field of HIV vaccine research, which had stalled after vaccines based on neutralizing antibody and cytotoxic T cells had failed to induce protection. A large post-vaccine research effort has focused attention on the role of non-neutralizing antibodies in the protection afforded by the RV144 vaccine. These binding antibodies can initiate immune responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and combine elements of the adaptive and innate immune system in the form of antibodies and effector cells (including NK cells, monocytes and granulocytes). A complex interplay exists between the variable portion of the binding antibody and its HIV antigen target on one hand and the constant region of the antibody and the Fcγ-receptor of the effector cell on the other hand. Technical advances have revolutionized the abilities of scientist to detect the targets of non-neutralizing antibodies, including both envelope and non-envelope epitopes, and their role in forcing escape. Our understanding of the antibody characteristics (including IgG subclasses and Fc glycan profile) is providing valuable insights into their optimal structure and function. We expand on critical research on ADCC effector cells, particularly education of NK cells. We introduce the concept of HIV antibodydependent trogocytosis by monocytes as a potentially important aspect of HIV immunity. In summary, this review highlights recent advances in HIV-specific antibody immunity mediated through NK cells and monocytes.
The High Cost of Fidelity
Publisher: Mary Ann Liebert Inc
Date: 2014
Serial study of lymph node cell subsets using fine needle aspiration in pigtail macaques
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.JIM.2013.05.005
Abstract: Lymphoid tissues are of intense interest for studies of the pathogenesis of human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques but are relatively difficult to s le non-invasively. Fine needle aspiration (FNA) cytology, conventionally a diagnostic procedure for lymphadenopathy, can be used for longitudinal study of tissue cell subsets during HIV/SIV infection. In this study, we serially s led lymph node (LN) FNA from pigtail macaques and studied cell subsets in the aspect of absolute count, frequency, and functionality by flow cytometry. The median recovered lymphocyte count from FNA s les was 2.01×10(5) (3.0×10(3) to 2.25×10(6), n=38) and median CD4+ T cell subset recovered was 5.94×10(4) (277 to 6.17×10(5), n=38). Although we observed a relatively large variation in the frequencies of cell subsets of FNA s les taken from different time points, the cell subset composition of FNA s les, in particular T cell and CD4+ T cell frequencies, was broadly comparable to whole excised LNs (n=6) and distinct from peripheral blood. A subset of CD4+ T cells that is located almost exclusively in secondary lymphoid tissues, T follicular helper (TFH) cells, was readily identifiable in LN FNAs and the TFH cell frequencies were strongly correlated with B cell frequencies. In vitro functionality of FNA lymphocytes was demonstrated using polyclonal SEB stimulation, resulting in a median 6% of responding CD4+ T cells, comparable to circulating CD4+ T lymphocytes. We conclude that serial s ling of macaque LNs using FNA is a potentially useful method to study the immunopathogenesis of SIV infection and may be extended to HIV infection.
A Role for Fc-Mediated Humoral Immunity in Reducing HIV Transmission Rates between HIV Serodiscordant Heterosexual Couples
Publisher: Elsevier BV
Date: 12-2017
Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies
Publisher: Springer Science and Business Media LLC
Date: 09-09-2020
DOI: 10.1038/S41564-020-00789-5
Abstract: Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.
Immunogenicity of prime-boost protein subunit vaccine strategies against SARS-CoV-2 in mice and macaques
Publisher: Springer Science and Business Media LLC
Date: 03-03-2021
DOI: 10.1038/S41467-021-21665-8
Abstract: SARS-CoV-2 vaccines are advancing into human clinical trials, with emphasis on eliciting high titres of neutralising antibodies against the viral spike (S). However, the merits of broadly targeting S versus focusing antibody onto the smaller receptor binding domain (RBD) are unclear. Here we assess prototypic S and RBD subunit vaccines in homologous or heterologous prime-boost regimens in mice and non-human primates. We find S is highly immunogenic in mice, while the comparatively poor immunogenicity of RBD is associated with limiting germinal centre and T follicular helper cell activity. Boosting S-primed mice with either S or RBD significantly augments neutralising titres, with RBD-focussing driving moderate improvement in serum neutralisation. In contrast, both S and RBD vaccines are comparably immunogenic in macaques, eliciting serological neutralising activity that generally exceed levels in convalescent humans. These studies confirm recombinant S proteins as promising vaccine candidates and highlight multiple pathways to achieving potent serological neutralisation.
Fowlpox virus vaccines for HIV and SHIV clinical and pre-clinical trials
Publisher: Elsevier BV
Date: 27-02-2006
DOI: 10.1016/J.VACCINE.2005.09.044
Abstract: DNA prime and recombinant fowlpox virus (rFPV) boost vaccines were designed to express multiple HIV or SIV antigens for use in human clinical trials and in pre-clinical trials in macaques. Three sets of vaccines with matching HIV or SIV antigen sets, modified for vaccine safety considerations, were constructed and shown to express the relevant proteins. The rFPV vaccines with inserts at up to three sites, were stable on passage in chick cell culture, including during GMP manufacture of vaccines for human Phase I clinical trials. Cellular and humoral immunogenicity in mice was demonstrated using a DNA prime/rFPV boost and vaccinia virus challenge model. These data establish a preliminary safety and efficacy profile for these multigenic vaccines suggesting they are suitable for advanced development as candidate HIV vaccines.
Analysis of Cytotoxic T Lymphocyte Responses to SIV Proteins in SIV-Infected Macaques Using Antigen-Specific Stimulation with Recombinant Vaccinia and Fowl Poxviruses
Publisher: Mary Ann Liebert Inc
Date: 05-1994
Abstract: Methods to analyze CD8+ CTL responses to simian immunodeficiency virus (SIV)-encoded proteins are essential to understand lentivirus immunopathogenesis and protective immune responses. Recombinant infectious shuttle vectors are useful for analyzing CTL responses to many viruses, including HIV. Therefore, CTL responses in SIV-infected Macaca fascicularis to SIV env and SIV gag ol were evaluated using specific antigen stimulation with recombinant vaccinia (rVV) and fowl poxviruses (rFPV) containing SIV genes. Peripheral blood mononuclear cells from SIV-infected animals were stimulated with autologous cells infected with rVV expressing SIV env/gag ol, and CTLs specific for SIV env and for SIV gag ol were detected by testing for lytic activity in target cells expressing these genes separately. Lymphocyte subset purifications from the effector population demonstrated that the CTL response was mediated by CD8+ cells, and the use of brefeldin A to selectively block antigen presentation in association with MHC class I products affirmed this cytolytic activity was class I restricted. The use of rVV to analyze responses to SIV genes is potentially problematic in hosts immunized to vaccinia. Fowl poxvirus is an alternative virus that has many of the molecular advantages of vaccinia virus but is genomically distinct. Therefore, the ability of rFPV to expand and detect SIV-specific CTLs was evaluated. Although there was no cytopathic effect following infection with rFPV, macaque cells infected with this vector did express rFPV gene products, and could be used as stimulator and target cells to detect SIV-specific CD8+ CTLs. The results suggest that these recombinant viral vectors can be used to specifically stimulate CD8+, MHC class I-restricted CTLs reactive to SIV proteins, and should facilitate evaluating CTL responses in both SIV-infected animals and animals vaccinated against SIV.
Vaccination with Attenuated Simian Immunodeficiency Virus by DNA Inoculation
Publisher: American Society for Microbiology
Date: 12-2001
DOI: 10.1128/JVI.75.23.11930-11934.2001
Abstract: Delivering attenuated lentivirus vaccines as proviral DNA would be simple and inexpensive. Inoculation of macaques with wild-type simian immunodeficiency virus strain mac239 (SIV mac239 ) DNA or SIV mac239 DNA containing a single deletion in the 3′ nef -long terminal repeat overlap region ( nef /LTR) led to sustained SIV infections and AIDS. Injection of SIV mac239 DNA containing identical deletions in both the 5′ LTR and 3′ nef /LTR resulted in attenuated SIV infections and substantial protection against subsequent mucosal SIV mac251 challenge.
Fc functional antibodies in humans with severe H7N9 and seasonal influenza
Publisher: American Society for Clinical Investigation
Date: 06-07-2017
Anti-SIV Cytolytic Molecules in Pigtail Macaques
Publisher: Mary Ann Liebert Inc
Date: 08-2008
Abstract: Release of granzymes and perforin from the cytolytic granules of SIV-specific CD8 T cells is a critically important effector mechanism facilitating the elimination of SIV-infected cells. We sequenced granzyme A, B, and K and perforin in pigtail macaques and defined polymorphisms between humans, rhesus macaques, and pigtail macaques. The pigtail macaque sequences were similar to the corresponding rhesus sequences at the mRNA and protein level and (0.4-1.1% sequence differences) but substantially different from human sequences (3.8-8.1% sequence differences). We used this sequence information to develop multiplex PCR assays to detect these genes. We also successfully studied the release of perforin and granzyme B from deregulating SIV-specific CD8 T cells by flow cytometry. These sequences and tools enable further study of the cytolytic control of SIV in pigtail macaques.
Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets
Publisher: American Society for Microbiology
Date: 15-03-2008
DOI: 10.1128/JVI.01153-07
Abstract: GB virus B (GBV-B) is a hepatotropic virus that is closely related to hepatitis C virus (HCV). GBV-B causes acute hepatitis in infected marmosets and tamarins and is therefore a useful small-animal model for the study of HCV. We investigated virus-specific T-cell responses in marmosets infected with GBV-B. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses in the peripheral blood of two marmosets were assessed throughout the course of GBV-B infection. These T-cell responses were directed against the GBV-B nonstructural proteins 3 (NS3), 4A (NS4A), and 5B (NS5B), and their appearance was temporally associated with clearance of viremia. These marmosets were then rechallenged with GBV-B at least 3 months after clearance of the primary infection to determine if the animals were protected from reinfection. There was no detectable viremia following reinfection, although a sharp increase in T-cell responses against GBV-B proteins was observed. Epitope mapping of T-cell responses to GBV-B was performed with liver and blood s les from both marmosets after rechallenge with GBV-B. Three shared, immunodominant T-cell epitopes within NS3 were identified in animals with multiple common major histocompatibility complex class I alleles. IFN-γ ELISPOT responses were also detected in the livers of two marmosets that had resolved a primary GBV-B infection. These responses were high in frequency and were directed against epitopes within GBV-B NS3, NS4A, and NS5B proteins. These results indicate that virus-specific T-cell responses are detectable in the liver and blood of GBV-B-infected marmosets and that the clearance of GBV-B is associated with the appearance of these responses.
The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV
Publisher: Mary Ann Liebert Inc
Date: 09-2018
Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice
Publisher: Proceedings of the National Academy of Sciences
Date: 23-04-2021
Abstract: Neutralizing antibodies are important for immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as therapeutics for the prevention and treatment of COVID-19. We identified high-affinity nanobodies against SARS-CoV-2 receptor-binding domain and found that nanobody cocktails consisting of two noncompeting nanobodies were able to block ACE2 engagement with RBD variants present in human populations and potently neutralize both wild-type SARS-CoV-2 and the N501Y D614G variant at low concentrations. Prophylactic administration of nanobody cocktails reduced viral loads in mice infected with the N501Y D614G SARS-CoV-2 virus, showing that nanobody cocktails are useful as prophylactic agents against SARS-CoV-2.
Comparison of influenza and SIV specific CD8 T cell responses in macaques.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2012
Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity in Intravenous Immunoglobulin as a Potential Therapeutic Against Emerging Influenza Viruses
Publisher: Oxford University Press (OUP)
Date: 10-06-2014
Abstract: Intravenous immunoglobulin (IVIG) is a purified pool of human antibodies from thousands of donors that is used to prevent or treat primary immune deficiency, several infectious diseases, and autoimmune diseases. The antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against heterologous influenza strains may be present in IVIG preparations. We tested 8 IVIG preparations prior to the 2009 H1N1 swine-origin influenza pandemic and 10 IVIG preparations made after 2010 for their ability to mediate influenza-specific ADCC. ADCC mediating antibodies to A(H1N1)pdm09 hemagglutinin (HA) and neuraminidase (NA) were detected in IVIG preparations prior to the 2009-H1N1 pandemic. The HA-specific ADCC targeted both the HA1 and HA2 regions of A(H1N1)pdm09 HA and was capable of recognizing a broad range of HA proteins including those from recent avian influenza strains A(H5N1) and A(H7N9). The low but detectable ADCC recognition of A(H7N9) was likely due to rare in iduals in the population contributing cross-reactive antibodies to IVIG. IVIG preparations contain broadly cross-reactive ADCC mediating antibodies. IVIG may provide at least some level of protection for in iduals at high risk of severe influenza disease, especially during influenza pandemics prior to the development of effective vaccines.
High fidelity simian immunodeficiency virus reverse transcriptase mutants have impaired replication in vitro and in vivo
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.VIROL.2016.02.008
Abstract: The low fidelity of HIV replication facilitates immune and drug escape. Some reverse transcriptase (RT) inhibitor drug-resistance mutations increase RT fidelity in biochemical assays but their effect during viral replication is unclear. We investigated the effect of RT mutations K65R, Q151N and V148I on SIV replication and fidelity in vitro, along with SIV replication in pigtailed macaques. SIVmac239-K65R and SIVmac239-V148I viruses had reduced replication capacity compared to wild-type SIVmac239. Direct virus competition assays demonstrated a rank order of wild-type>K65R>V148I mutants in terms of viral fitness. In single round in vitro-replication assays, SIVmac239-K65R demonstrated significantly higher fidelity than wild-type, and rapidly reverted to wild-type following infection of macaques. In contrast, SIVmac239-Q151N was replication incompetent in vitro and in pigtailed macaques. Thus, we showed that RT mutants, and specifically the common K65R drug-resistance mutation, had impaired replication capacity and higher fidelity. These results have implications for the pathogenesis of drug-resistant HIV.
Robust and prototypical immune responses toward influenza vaccines in the high-risk group of Indigenous Australians
Publisher: Proceedings of the National Academy of Sciences
Date: 04-10-2021
Abstract: Indigenous populations worldwide are highly susceptible to influenza virus infections. Vaccination with inactivated virus is highly recommended to protect Indigenous populations, including Indigenous Australians. There is no study to date that assessed immune responses induced by the inactivated seasonal influenza vaccine in the Indigenous population. Vaccine recommendations are thus based on data generated for non-Indigenous populations and might not be representative for Indigenous people. We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of cT FH 1 cells at the acute response strongly correlating with total change of antibody vaccine titers induced by vaccination. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and subsequent complications.
AIDS Vaccine for Asia Network (AVAN): Expanding the Regional Role in Developing HIV Vaccines
Publisher: Public Library of Science (PLoS)
Date: 21-09-2010
Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo
Publisher: Public Library of Science (PLoS)
Date: 25-01-2008
Short Communication: Antibody Responses to Human Immunodeficiency Virus Envelope from Infections with Multiple Subtypes Utilize the 1F7-Idiotypic Repertoire
Publisher: Mary Ann Liebert Inc
Date: 05-2013
Mechanically tunable, self-adjuvanting nanoengineered polypeptide particles
Publisher: Wiley
Date: 10-05-2013
Abstract: DNA-loaded polypeptide particles are prepared via templated assembly of mesoporous silica for the delivery of adjuvants. The elasticity and cargo-loading capacity of the obtained particles can be tuned by the amount of cross-linker used to stabilize the polypeptide particles. The use of polypeptide particles as biocarriers provides a promising method for vaccine delivery.
Complexity of the Inoculum Determines the Rate of Reversion of SIV Gag CD8 T Cell Mutant Virus and Outcome of Infection
Publisher: Public Library of Science (PLoS)
Date: 10-04-2009
Quantification of Simian Immunodeficiency Virus Cytotoxic T Lymphocyte Escape Mutant Viruses
Publisher: Mary Ann Liebert Inc
Date: 08-2008
Abstract: Escape from cytotoxic T-lymphocyte (CTL) pressure is common in HIV-1 infection of humans and simian immunodeficiency virus (SIV) infections of macaques. CTL escape typically incurs a fitness cost as reversion back to wild-type can occur upon transmission. We utilized sequence-specific primers and DNA probes with real-time polymerase chain reaction (PCR) to sensitively and specifically track wild-type and escape mutant viremia at the Mane-A*17-restricted SIV Gag(371379) epitope AF9 in pigtail macaques. The generation of minor escape mutant populations is detected by the real-time PCR 2 weeks earlier than observed using standard sequencing techniques. We passaged the AF9 CTL escape mutant virus into two naïve Mane-A*17-negative pigtail macaques and showed that reversion to wild-type was rapid during acute infection and then slowed considerably at later stages of the infection. These data help refine our understanding of how CTL escape mutant viruses evolve.
MAIT cells are depleted early but retain functional cytokine expression in HIV infection
Publisher: Wiley
Date: 28-10-2015
DOI: 10.1038/ICB.2014.91
Abstract: Mucosal-associated invariant T (MAIT) cells home to mucosal sites and exert antimicrobial activity against bacteria and other microorganisms. HIV infection leads to early depletion of gut T cells and translocation of bacterial products. There are reports that MAIT cells, defined by coexpression of Vα7.2 and CD161, are depleted during HIV infection and residual MAIT cells are functionally impaired. However, one study suggested that MAIT cells might remain after HIV infection but evade detection through CD161 downregulation. Thus, the impact of HIV infection on MAIT cells is unclear. We studied longitudinal blood s les from 31 HIV-infected subjects for MAIT cell numbers, phenotype and function using both standard Vα7.2/CD161 surface markers and an MR1 tetramer. We found that MAIT cells were depleted early during HIV infection, and although there was a concomitant rise in Vα7.2(+)CD161(-) cells, these were MR1 tetramer negative, indicating that these are unlikely to be altered MAIT cells. Antigen-mediated activation of residual MAIT cells showed that they remained functional out to 2 years following HIV infection. Although MAIT cells are depleted in HIV infection, residual and functionally active MAIT cells persist and may still be able to assist in controlling bacterial translocation during HIV infection.
MAIT Cells Upregulate α4β7 in Response to Acute Simian Immunodeficiency Virus/Simian HIV Infection but Are Resistant to Peripheral Depletion in Pigtail Macaques
Publisher: The American Association of Immunologists
Date: 04-2019
Abstract: Mucosal-associated invariant T (MAIT) cells are nonconventional T lymphocytes that recognize bacterial metabolites presented by MR1. Whereas gut bacterial translocation and the loss/dysfunction of peripheral MAIT cells in HIV infection is well described, MAIT cells in nonhuman primate models are poorly characterized. We generated a pigtail macaque (PTM)–specific MR1 tetramer and characterized MAIT cells in serial s les from naive and SIV– or simian HIV–infected PTM. Although PTM MAIT cells generally resemble the phenotype and transcriptional profile of human MAIT cells, they exhibited uniquely low expression of the gut-homing marker α4β7 and were not enriched at the gut mucosa. PTM MAIT cells responded to SIV/simian HIV infection by proliferating and upregulating α4β7, coinciding with increased MAIT cell frequency in the rectum. By 36 wk of infection, PTM MAIT cells were activated and exhibited a loss of Tbet expression but were not depleted as in HIV infection. Our data suggest the following: 1) MAIT cell activation and exhaustion is uncoupled from the hallmark depletion of MAIT cells during HIV infection and 2) the lack of PTM MAIT cell enrichment at the gut mucosa may prevent depletion during chronic infection, providing a model to assess potential immunotherapeutic approaches to modify MAIT cell trafficking during HIV infection.
CD4- and time-dependent susceptibility of HIV-1-infected cells to ADCC.
Publisher: American Society for Microbiology
Date: 15-05-2019
DOI: 10.1128/JVI.01901-18
Abstract: An increasing body of evidence suggests that ADCC contributes to protection against HIV-1 acquisition and slower HIV-1 disease progression. Targeting cells early during the infection cycle would be most effective in limiting virus production and spread. We hypothesized that there could be a time-dependent susceptibility of HIV-1-infected cells to ADCC in regard to CD4 expression. We observed NK cell-mediated ADCC of HIV-1-infected cells at multiple stages of CD4 downregulation. Importantly, ADCC of early infected cells appeared to be driven by a previously unappreciated problem of soluble Env and virions from the viral inoculum sensitizing uninfected cells to ADCC prior to de novo Env expression. These results have implications for studies examining ADCC against cells with nascent HIV-1 infection.
Tracking the kinetics and phenotype of spike epitope-specific CD4 T cell immunity in the context of SARS-CoV-2 infection and vaccination
Publisher: Research Square Platform LLC
Date: 19-10-2021
DOI: 10.21203/RS.3.RS-957030/V1
Abstract: CD4+ T cells play a critical role in the immune response to viral infection. SARS-CoV-2 infection and vaccination elicit strong CD4+ T cell responses to the viral spike protein, including circulating T follicular helper (cTFH) cells that correlate with the development of neutralising antibodies. Here we use a novel HLA-DRB1*15:01/S751 tetramer to precisely track spike-specific CD4+ T cells following recovery from mild/moderate COVID-19, or after vaccination with spike-encoding vaccines. SARS-CoV-2 infection induces robust S751-specific responses with both CXCR5- and cTFH phenotypes that are maintained for at least 12 months in a stable, CXCR3-biased, central memory pool. Vaccination of immunologically naïve subjects similarly drives expansion of S751-specific T cells with a highly restricted TCR repertoire comprised of both public and private clonotypes. Vaccination of convalescent in iduals drives recall of CD4+ T cell clones established during infection, which are shared between the CXCR5- and cTFH compartments. This recall response is evident 5 days after antigen exposure and includes a population of spike-specific cTFH that persist in the periphery after losing expression of PD-1. Overall this study demonstrates the generation of a stable pool of cTFH and memory CD4+ T cells that can be recalled upon spike antigen re-exposure, which may play an important role in long-term protection against SARS-CoV-2 infection.
Antibody-dependent cellular cytotoxicity and influenza virus
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.COVIRO.2016.12.002
Abstract: Antibodies are a key defence against influenza infection and disease, but neutralizing antibodies are often strain-specific and of limited utility against ergent or pandemic viruses. There is now considerable evidence that influenza-specific antibodies with Fc-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), can assist in the clearance of influenza infection in vitro and in animal models. Further, ADCC-mediating antibodies that recognize a broad array of influenza strains are common in humans, likely as a result of being regularly exposed to influenza infections. The concept that influenza-specific ADCC can assist in the partial control of influenza infections in humans is gaining momentum. This review examines the utility of influenza-specific ADCC antibodies.
Antiretroviral therapy initiation in an Australian cohort: implications for increased use of antiretroviral therapy
Publisher: Springer Science and Business Media LLC
Date: 20-08-2014
DOI: 10.1007/S10096-014-2227-3
Abstract: Human immunodeficiency virus (HIV) management is entering a "universal test and treat" phase, although the benefits from this approach in developed world scenarios are uncertain. We analyzed 79 combination anti-retroviral therapy (cART)-naïve HIV-positive in iduals who were intensively prospectively followed from 2004 to 2013. We studied HIV-related illnesses, potential HIV transmissions, impact on sexual behavior, and factors impeding earlier cART initiation. Sixty-eight (86 %) subjects commenced cART at a mean of 6.0 years after diagnosis: 71 % with a CD4 T-cell count <350 cells/μl. A significant minority of subjects (29 %) resisted initiation of cART despite physician recommendation for a mean of 18 months. Only one HIV-related illness occurred in a patient who had not previously recorded a CD4 T-cell count <500 cell/μl, totaling 195 person-years of observation. A 40 % increase in sexually transmitted infections (STIs) occurred after commencing cART. We detected six HIV transmissions in our cohort, all of which were before initiating cART and 5 of them had a prior CD4 T-cell count <500 cells/μl. Illnesses related to cART deferral were rare and most HIV transmissions we detected occurred in people with a prior CD4 T-cell count <500 cells/μl. Our study raises concerns about increasing STI rates after cART initiation. Focusing resources on cART initiation among patients with CD4 T-cell counts <500 cells/μl and enhancing safe sexual practices should remain a priority.
Protective efficacy of the anti-HIV broadly neutralizing antibody PGT121 in the context of semen exposure
Publisher: Elsevier BV
Date: 08-2021
Mucosally-administered human-simian immunodeficiency virus DNA and fowlpoxvirus-based recombinant vaccines reduce acute phase viral replication in macaques following vaginal challenge with CCR5-tropic SHIVSF162P3
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.VACCINE.2005.05.032
Abstract: Further advances are required in understanding protection from AIDS by T cell immunity across mucosal sites of virus transmission. We analysed a set of multigenic HIV and SHIV DNA and Fowlpoxvirus (FPV) prime and boost vaccines for immunogenicity and protective efficacy in outbred pigtail macaques when delivered via mucosal surfaces (intranasally or intrarectally). Intranasally delivered DNA, even when adjuvanted and given as a fine droplet spray, was neither immunogenic nor protective in macaques. Some protection from acute infection with a pathogenic vaginal SHIVSF162P3 challenge was, however, observed with a regimen involving intramuscular DNA vaccine priming followed by either intranasally or intrarectally delivered rFPV boosting. Interestingly, animals boosted with rFPV vaccine via either of these mucosal routes had poor circulating T cell responses prior to challenge with SHIV compared to those boosted via the intramuscular route. Nevertheless, the mucosally-vaccinated animals generated equivalent anamnestic mucosal and systemic SHIV-specific CD4 and CD8 T cell responses following SHIV administration, with significant reduction in acute plasma viremia against this vaginal challenge. Our data suggest strategies for effective priming of partial immunity to mucosal HIV-1 exposure utilizing systemic prime and mucosal boost vaccination strategies.
Isotype-switched immunoglobulin G antibodies to HIV Gag proteins may provide alternative or additional immune responses to 'protective' human leukocyte antigen-B alleles in HIV controllers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-02-2013
Tear antibodies to SARS-CoV-2: implications for transmission
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1354
Abstract: SARS‐CoV‐2 can be transmitted by aerosols, and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS‐CoV‐2 in tears after infection or vaccination. We analysed the SARS‐CoV‐2‐specific IgG and IgA responses in human tears after either COVID‐19 infection or vaccination. We measured the antibody responses in 16 subjects with COVID‐19 infection for an average of 7 months before, and 15 subjects before and 2 weeks post‐Comirnaty (Pfizer‐BioNtech) vaccination. Plasma, saliva and basal tears were collected. Eleven pre‐pandemic in iduals were included as healthy controls. IgG antibodies to spike and nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS‐CoV‐2 infection in comparison with uninfected controls. While receptor‐binding domain (RBD)‐specific antibodies were detected in plasma, minimal RBD‐specific antibodies were detected in tears and saliva. By contrast, high levels of IgG antibodies to spike and RBD, but not nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS‐CoV‐2 antigens were detected in plasma following infection or vaccination but were unchanged in tears and saliva. Comirnaty vaccination induced high neutralising Abs in the plasma, but limited neutralising antibodies were detected in saliva or tears. Both infection and vaccination induce SARS‐CoV‐2‐specific IgG antibodies in tears. RBD‐specific IgG antibodies in tears were induced by vaccination but were not present 7 months post‐infection. This suggests the neutralising antibodies may be low in the tears late following infection.
The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1
Publisher: Frontiers Media SA
Date: 20-08-2018
Serological and cellular inflammatory signatures in end-stage kidney disease and latent tuberculosis
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1355
Abstract: Tuberculosis comorbidity with chronic diseases including diabetes, HIV and chronic kidney disease is of rising concern. In particular, latent tuberculosis infection (LTBI) comorbidity with end‐stage kidney disease (ESKD) is associated with up to 52.5‐fold increased risk of TB reactivation to active tuberculosis infection (ATBI). The immunological mechanisms driving this significant rise in TB reactivation are poorly understood. To contribute to this understanding, we performed a comprehensive assessment of soluble and cellular immune features amongst a unique cohort of patients comorbid with ESKD and LTBI. We assessed the plasma and cellular immune profiles from patients with and without ESKD and/or LTBI ( N = 40). We characterised antibody glycosylation, serum complement and cytokine levels. We also assessed classical and non‐classical monocytes and T cells with flow cytometry. Using a systems‐based approach, we identified key immunological features that discriminate between the different disease states. In iduals with ESKD exhibited a highly inflammatory plasma profile and an activated cellular state compared with those without ESKD, including higher levels of inflammatory antibody Fc glycosylation structures and activated CX3CR1 + monocytes that correlate with increased inflammatory plasma cytokines. Similar elevated inflammatory signatures were also observed in ESKD + /LTBI + compared with ESKD − /LTBI + , suggesting that ESKD induces an overwhelming inflammatory immune state. In contrast, no significant inflammatory differences were observed when comparing LTBI + and LTBI − in iduals. Our study highlights the highly inflammatory state induced by ESKD. We hypothesise that this inflammatory state could contribute to the increased risk of TB reactivation in ESKD patients.
Anti‐HIV ‐1 antibody‐dependent cellular cytotoxicity mediated by hyperimmune bovine colostrum I gG
Publisher: Wiley
Date: 28-08-2012
Abstract: Antibodies with antibody-dependent cellular cytotoxicity (ADCC) activity play an important role in protection against HIV-1 infection, but generating sufficient amounts of antibodies to study their protective efficacy is difficult. HIV-specific IgG can be easily and inexpensively produced in large quantities using bovine colostrum. We previously vaccinated cows with HIV-1 envelope gp140 and elicited high titers of anti-gp140-binding IgG in colostrum. In the present study, we determined whether bovine antibodies would also demonstrate specific cytotoxic activity. We found that bovine IgG bind to Fcγ-receptors (FcγRs) on human neutrophils, monocytes, and NK cells in a dose-dependent manner. Antibody-dependent killing was observed in the presence of anti-HIV-1 colostrum IgG but not nonimmune colostrum IgG. Killing was dependent on Fc and FcγR interaction since ADDC activity was not seen with F(ab')(2) fragments. ADCC activity was primarily mediated by CD14(+) monocytes with FcγRIIa (CD32a) as the major receptor responsible for monocyte-mediated ADCC in response to bovine IgG. In conclusion, we demonstrate that bovine anti-HIV colostrum IgG have robust HIV-1-specific ADCC activity and therefore offer a useful source of antibodies able to provide a rapid and potent response against HIV-1 infection. This could assist the development of novel Ab-mediated approaches for prevention of HIV-1 transmission.
Neutralising antibodies predict protection from severe COVID-19
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.09.22275942
Abstract: Background: Vaccine protection from COVID-19 has been shown to decline with time-since-vaccination and against SARS-CoV-2 variants. Protection against severe COVID-19 is higher than against symptomatic infection, and also appears relatively preserved over time and against variants. Although Protection protection from symptomatic SARS-CoV-2 infection has been shown to be strongly correlated with neutralising antibody titres, however, this relationship has been is less well described for severe COVID-19. Protection against severe COVID-19 is higher than against symptomatic infection, and also appears relatively preserved over time and against variants. Here we analyse whether neutralising antibody titre remains predictive of protection against severe COVID-19 in the face of waning neutralising antibody levels and emerging variants. Methods: We extracted data from 15 studies reporting on protection against a range of SARS-CoV-2 clinical endpoints ("any infection", "symptomatic infection" and "severe COVID-19"). We then estimated the concurrent neutralising antibody titres using existing parameters on vaccine potency, neutralising antibody decay, and loss of recognition of variants and investigated the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. Findings: Predicted neutralising antibody titres are strongly correlated with vaccine effectiveness against symptomatic and severe COVID-19 (Spearman rho = .94 and 0.63 respectively, p .001 for both), consistent with previous estimates of the relationship between neutralisation and protection. Indeed 82% (137 of 167) of reported values of protection against severe COVID-19 across a range of vaccines and variants lie within the 95% confidence intervals of the published model. Interpretation: Neutralising antibody titres are predictive of vaccine effectiveness against severe COVID-19 including in realistic scenarios of waning immunity and viral variants. Funding: National Health and Medical Research Council (Australia), Medical Research Future Fund (Australia).
Nucleic acid vaccines: tasks and tactics.
Publisher: Springer Science and Business Media LLC
Date: 2001
DOI: 10.1385/IR:24:3:225
What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins
Publisher: Elsevier BV
Date: 06-2016
Monoclonal antibody levels and protection from COVID-19
Publisher: Springer Science and Business Media LLC
Date: 28-07-2023
DOI: 10.1038/S41467-023-40204-1
Abstract: Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies (mAb) in preventing symptomatic SARS-CoV-2 infection. We use data on the in vivo concentration of mAb and the associated protection from COVID-19 over time to model the dose-response relationship of mAb for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a mAb concentration of 96-fold of the in vitro IC50 (95% CI: 32—285). This relationship provides a tool for predicting the prophylactic efficacy of new mAb and against SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either mAb treatment or vaccination. We find no significant difference between the 50% protective titer for mAb and vaccination, although s le sizes limited the power to detect a difference.
Understanding the Role of Mucosal-Associated Invariant T-Cells in Non-human Primate Models of HIV Infection
Publisher: Frontiers Media SA
Date: 18-08-2020
Improving immunological insights into the ferret model of human viral infectious disease
Publisher: Wiley
Date: 03-10-2019
DOI: 10.1111/IRV.12687
Rates of HIV immune escape and reversion: implications for vaccination
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.TIM.2008.09.001
Abstract: HIV-1 mutates extensively in vivo to escape immune control by CD8+ T cells (CTLs). The CTL escape mutant virus might also revert back to wild-type upon transmission to new hosts if significant fitness costs are incurred by the mutation. Immune escape and reversion can be extremely fast if they occur very early after infection, whereas they are much slower when they begin later during infection. Immune escape presents a significant barrier to vaccination, because escape of vaccine-mediated immune responses could neutralise any benefits of vaccination. Here, we consider the dynamics of immune escape and reversion in vivo in natural infection, and suggest how understanding of this can be used to predict optimal vaccine targets and design vaccination strategies that maximise immune control. We predict that inducing synchronous, broad CTL by vaccination should limit the likelihood of viral escape from immune control.
Slaying the Trojan horse: natural killer cells exhibit robust anti-HIV-1 antibody-dependent activation and cytolysis against allogeneic T cells.
Publisher: American Society for Microbiology
Date: 2014
DOI: 10.1128/JVI.02461-14
Abstract: Many attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus both in vitro and in vivo . Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1 + NK cell subset from HLA-Bw4 + in iduals exhibits an activation advantage over the KIR3DL1 − subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines. IMPORTANCE NK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.
Poor protective potential of influenza nucleoprotein antibodies despite wide prevalence
Publisher: Wiley
Date: 09-11-2021
DOI: 10.1111/IMCB.12508
Abstract: Humans are exposed to influenza virus through periodic infections. Due to these repeated exposures, human populations commonly have elevated antibody titers targeting the conserved internal influenza virus nucleoprotein (NP). Despite the presence of anti‐NP antibodies, humans are acutely susceptible to drifted influenza viruses with antigenically different surface proteins and the protective potential of human NP antibodies is unclear. In this study, high levels of anti‐NP antibody and NP‐specific B cells were detected in both adult humans and influenza‐infected mice, confirming that NP is a major target of humoral immunity. Through sorting single B cells from influenza‐exposed human adults, we generated a panel of 11 anti‐NP monoclonal antibodies (mAbs). The majority of anti‐NP human mAbs generated were capable of engaging cellular Fc receptors and bound NP on the surface of influenza‐infected cell lines in vitro , suggesting that anti‐NP mAbs have the potential to mediate downstream Fc effector functions such as antibody‐dependent cellular cytotoxicity and antibody‐dependent phagocytosis. However, human anti‐NP mAbs were not protective in vivo when passively transferred into a murine influenza challenge model. Future in vivo studies examining the synergistic effect of anti‐NP mAbs infused with other influenza‐specific mAbs are warranted.
Circulating T
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-02-2018
DOI: 10.1126/SCITRANSLMED.AAN8405
Abstract: Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections. IIV activates B cells and T follicular helper (T
Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations
Publisher: American Society for Clinical Investigation
Date: 10-04-2023
Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates
Publisher: Wiley
Date: 14-01-2015
Abstract: Targeting antigens to dendritic cell (DC) surface receptors using antibodies has been successfully used to generate strong immune responses and is currently in clinical trials for cancer immunotherapy. Whilst cancer immunotherapy focuses on the induction of CD8(+) T-cell responses, many successful vaccines to pathogens or their toxins utilize humoral immunity as the primary effector mechanism. Universally, these approaches have used adjuvants or pathogen material that augment humoral responses. However, adjuvants are associated with safety issues. One approach, successfully used in the mouse, to generate strong humoral responses in the absence of adjuvant is to target antigen to Clec9A, also known as DNGR-1, a receptor on CD8α(+) DCs. Here, we address two issues relating to clinical application. First, we address the issue of variable adjuvant-dependence for different antibodies targeting mouse Clec9A. We show that multiple sites on Clec9A can be successfully targeted, but that strong in vivo binding and provision of suitable helper T cell determinants was essential for efficacy. Second, we show that induction of humoral immunity to CLEC9A-targeted antigens is extremely effective in nonhuman primates, in an adjuvant-free setting. Our findings support extending this vaccination approach to humans and offer important insights into targeting design.
Circulating effector γδ T cell populations are associated with acute coronavirus disease 19 in unvaccinated individuals
Publisher: Wiley
Date: 19-02-2023
DOI: 10.1111/IMCB.12623
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causes severe coronavirus disease 2019 (COVID‐19) in a small proportion of infected in iduals. The immune system plays an important role in the defense against SARS‐CoV‐2, but our understanding of the cellular immune parameters that contribute to severe COVID‐19 disease is incomplete. Here, we show that populations of effector γδ T cells are associated with COVID‐19 in unvaccinated patients with acute disease. We found that circulating CD27 neg CD45RA + CX3CR1 + Vδ1 effector cells expressing Granzymes (Gzms) were enriched in COVID‐19 patients with acute disease. Moreover, higher frequencies of GzmB + Vδ2 + T cells were observed in acute COVID‐19 patients. SARS‐CoV‐2 infection did not alter the γδ T cell receptor repertoire of either Vδ1 + or Vδ2 + subsets. Our work demonstrates an association between effector populations of γδ T cells and acute COVID‐19 in unvaccinated in iduals.
Functional advantage of educated KIR2DL1(+) natural killer cells for anti-HIV-1 antibody-dependent activation.
Publisher: Oxford University Press (OUP)
Date: 04-02-2016
DOI: 10.1111/CEI.12752
Abstract: Evidence from the RV144 HIV-1 vaccine trial implicates anti-HIV-1 antibody-dependent cellular cytotoxicity (ADCC) in vaccine-conferred protection from infection. Among effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody-dependent manner is reliant upon several factors. In general, NK cell-mediated antibody-dependent activation is most robust in terminally differentiated CD57+ NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I [MHC-I or human leucocyte antigen (HLA-I)] ligands. With regard to anti-HIV-1 antibody-dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA-Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA–C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA-I-devoid target cells or antibody-dependent stimulation with HIV-1 gp140-pulsed CEM.NKr-CCR5 target cells in the presence of an anti-HIV-1 antibody source. Among donors carrying the HLA-C2 ligand for KIR2DL1, higher interferon (IFN)-γ production was observed within KIR2DL1+ NK cells than in KIR2DL1– NK cells upon both direct and antibody-dependent stimulation. No differences in KIR2DL1+ and KIR2DL1– NK cell activation were observed in HLA-C1 homozygous donors. Additionally, higher activation in KIR2DL1+ than KIR2DL1– NK cells from HLA–C2 carrying donors was observed within less differentiated CD57– NK cells, demonstrating that the observed differences were due to education and not an overabundance of KIR2DL1+ NK cells within differentiated CD57+ NK cells. These observations are relevant for understanding the regulation of anti-HIV-1 antibody-dependent NK cell responses.
Differential cross-reactivity to the influenza B virus haemagglutinin underpins lineage-specific susceptibility between birth cohorts
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.25.554879
Abstract: Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that engender differential cross-reactivity to future influenza viruses, but direct serological evidence linked to susceptibility is limited. We analysed hemagglutination-inhibition titres in 1451 cross-sectional s les collected between 1992-2020, from in iduals born between 1917-2008, against influenza B virus (IBV) isolates from 1940-2021, including ‘future’ isolates that circulated after s le collection. We demonstrate that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the two IBV antigenic lineages, explaining lineage-specific age distributions of observed medically attended IBV infections. Our data bridge a critical gap between early life exposure, cross-reactivity, and influenza epidemiology and identify a plausible model to further dissect the interplay between host immunity, viral evolution and epidemiology.
What Can Gamma Delta T Cells Contribute to an HIV Cure?
Publisher: Frontiers Media SA
Date: 19-05-2020
Hemagglutinin Functionalized Liposomal Vaccines Enhance Germinal Center and Follicular Helper T Cell Immunity
Publisher: Wiley
Date: 09-03-2021
Related Organisations
Related Funding Activities
Linkage Projects - Grant ID: LP0991498
Start Date: 06-2011
End Date: 06-2014
Amount: $156,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE110100106
Start Date: 07-2011
End Date: 12-2012
Amount: $350,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP0987339
Start Date: 2009
End Date: 12-2012
Amount: $510,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP200100231
Start Date: 2020
End Date: 11-2023
Amount: $450,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE180100163
Start Date: 2018
End Date: 12-2018
Amount: $639,369.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP210103114
Start Date: 05-2021
End Date: 05-2024
Amount: $676,622.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0775612
Start Date: 2007
End Date: 12-2008
Amount: $700,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE120100131
Start Date: 02-2012
End Date: 02-2013
Amount: $150,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE200100163
Start Date: 06-2020
End Date: 05-2022
Amount: $700,000.00
Funder: Australian Research Council
View Funded ActivityARC Centres Of Excellence - Grant ID: CE140100036
Start Date: 06-2014
End Date: 06-2021
Amount: $26,000,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0989341
Start Date: 10-2009
End Date: 12-2010
Amount: $690,000.00
Funder: Australian Research Council
View Funded Activity