Miles Davenport

NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination

Publisher: Elsevier BV

Date: 02-2013

DOI: 10.1016/J.IMBIO.2012.04.003

Abstract: Semi-invariant T cell receptors (TCRs) found on natural killer T (NKT) and mucosal-associated invariant T (MAIT) cells are characterized by the use of invariant variable (V) and joining (J) gene combinations in the TCR α-chain, as well as ubiquitous canonical TCRα amino acid sequences that are dominant in many in iduals and similar across species. That they are so prevalent indicates that they occupy an important niche within the immune system. However, these TCRs are produced by a largely random gene recombination process, which seems a risky approach for the immune system to acquire these innate-like cells. We surveyed studies reporting NKT and MAIT TCRα sequences for six and four different species, respectively. Although the germline nature of the canonical human and mouse NKT and mouse MAIT TCRα sequences and an overlap of nucleotides between the mouse MAIT-related Vα and Jα genes have been noted in previous studies, in this study we demonstrate that, for all reported species, the canonical TCRα amino acid sequences can be encoded by at least one germline-derived nucleotide sequence. Moreover, these nucleotide sequences can utilize an overlap between the Vα and Jα genes in their production, which enables them to be produced by a large variety of recombination mechanisms. We investigated the role of these TCRα features in the production of the canonical NKT and MAIT TCRα sequences. In computer simulations of a random recombination process involving the invariant NKT and MAIT TCRα gene combinations for each species, the canonical NKT and MAIT TCRα sequences were the first or second most generated of all sequences with the CDR3α length restrictions associated with NKT and MAIT cells. These results suggest that the immune machinery enables the canonical NKT and MAIT TCRα sequences to be produced with great efficiency through the process of convergent recombination, ensuring their prevalence across in iduals and species.

Simian-Human Immunodeficiency Infection – Is the Course Set in the Acute Phase?

Publisher: Public Library of Science (PLoS)

Date: 17-02-2011

DOI: 10.1371/JOURNAL.PONE.0017180

Stochastic Expansions Maintain the Clonal Stability of CD8+ T Cell Populations Undergoing Memory Inflation Driven by Murine Cytomegalovirus

Publisher: The American Association of Immunologists

Date: 2020

DOI: 10.4049/JIMMUNOL.1900455

Abstract: CMV is an obligate and persistent intracellular pathogen that continually drives the production of highly differentiated virus-specific CD8+ T cells in an Ag-dependent manner, a phenomenon known as memory inflation. Extensive proliferation is required to generate and maintain inflationary CD8+ T cell populations, which are counterintuitively short-lived and typically exposed to limited amounts of Ag during the chronic phase of infection. An apparent discrepancy therefore exists between the magnitude of expansion and the requirement for ongoing immunogenic stimulation. To address this issue, we explored the clonal dynamics of memory inflation. First, we tracked congenically marked OT-I cell populations in recipient mice infected with murine CMV (MCMV) expressing the cognate Ag OVA. Irrespective of numerical dominance, stochastic expansions were observed in each population, such that dominant and subdominant OT-I cells were maintained at stable frequencies over time. Second, we characterized endogenous CD8+ T cell populations specific for two classic inflationary epitopes, M38 and IE3. Multiple clonotypes simultaneously underwent Ag-driven proliferation during latent infection with MCMV. In addition, the corresponding CD8+ T cell repertoires were stable over time and dominated by persistent clonotypes, many of which also occurred in more than one mouse. Collectively, these data suggest that stochastic encounters with Ag occur frequently enough to maintain oligoclonal populations of inflationary CD8+ T cells, despite intrinsic constraints on epitope display at in idual sites of infection with MCMV.

A distinctive peptide binding motif for HLA-DRB1 * 0407, an HLA-DR4 subtype not associated with rheumatoid arthritis

Publisher: Springer Science and Business Media LLC

Date: 13-01-1997

DOI: 10.1007/S002510050196

Abstract: In this study of microfinance institutions (MFIs) and their participants, we show how certain innovations made by MFIs during the COVID-19 pandemic enable further consolidation of NGOs in Bangladeshi society. The study is based on interviews conducted in 2020 with key personnel from three major NGOs in Bangladesh: Grameen, Sajida Foundation, and Brac (which is also the largest NGO in the world), as well as 20 interviews conducted in 2018 (before the pandemic) with microcredit recipients who use financial services. We observed that MFIs scaled up by taking on the function of relief provision, financial services became more entrenched, and NGO governance was bolstered as MFIs served as intermediaries between the state and people, even though, as the 2018 interviews reveal, microfinance participants were reticent about technology uptake.

Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty

Publisher: Wiley

Date: 12-2003

DOI: 10.1046/J.1440-1711.2003.01191.X

Abstract: Analysing T-cell receptor excision circle numbers in healthy in iduals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for in iduals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older in iduals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for in iduals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.

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.

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.

A novel fluorescent-based assay reveals that thrombopoietin signaling and Bcl-XL influence, respectively, platelet and erythrocyte lifespans

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.EXPHEM.2010.03.003

Abstract: The factors determining platelet and erythrocyte lifespan are not completely understood, despite extensive study. The lack of success may be attributed to the methods used to measure lifespan kinetics, all of which require processing of cells prior to analysis, and the inconsistent and potentially inappropriate use of mathematical models for data analysis. The aims of this study were to establish an in vivo platelet and erythrocyte labeling method using carboxyfluorescein diacetate succinimidyl ester (CFSE), determine the most appropriate mathematical model for lifespan analysis, and apply both to the study of factors that control platelet and erythrocyte lifespans. Control, c-mpl knockout (KO), and Bcl-X(L) mutant mice were injected with CFSE and platelet and erythrocyte fluorescence followed over time. Datasets were analyzed using linear, exponential, multiple-hit, and lognormal mathematical models. In vivo CFSE labeling of platelets and erythrocytes requires no postcollection processing, proved stable, nontoxic, nonimmunogenic, and the lifespans were highly reproducible. Mathematical modeling revealed the lognormal model gave a robust fit to control and extreme datasets when either extrinsic or intrinsic factors determined lifespan. Using these methods, platelet lifespans were found to be significantly shortened in thrombopoietin-receptor-deficient mice independent of blood loss, and the antiapoptotic protein Bcl-X(L) was shown to play a role in prolonging erythrocyte lifespans. The simultaneous study of platelet and erythrocyte lifespans using in vivo CFSE labeling with lognormal modeling yielded insight into common intrinsic and extrinsic platelet and erythrocyte lifespan determinants and provides an improved methodology for use in this field of research.

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.

Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites

Publisher: Cold Spring Harbor Laboratory

Date: 19-08-2021

DOI: 10.1101/2021.08.18.456784

Abstract: Maturation rate of malaria parasites within red blood cells (RBC) can be influenced by host nutrient status or circadian rhythm. Here, we observed in mice that systemic host inflammation, induced by lipopolysaccharide (LPS) conditioning or ongoing acute malaria infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. LPS-conditioning and acute infection both triggered substantial changes to the metabolomic composition of plasma in which parasites circulated. This altered plasma directly slowed parasite maturation in a manner that could not be rescued by supplementation, consistent with the presence of inhibitory factors. Single-cell transcriptomic assessment of mixed parasite populations, exposed to a short period of systemic host inflammation in vivo , revealed specific impairment in the transcriptional activity and translational capacity of trophozoites compared to rings or schizonts. Thus, we provide in vivo evidence of transcriptomic and phenotypic plasticity of asexual blood-stage Plasmodium parasites when exposed to systemic host inflammation.

Impact of fluctuation in frequency of human immunodeficiency virus/simian immunodeficiency virus reactivation during antiretroviral therapy interruption

Publisher: The Royal Society

Date: 19-08-2020

DOI: 10.1098/RSPB.2020.0354

Abstract: Antiretroviral therapy (ART) provides effective control of human immunodeficiency virus (HIV) replication and maintains viral loads of HIV at undetectable levels. Interruption of ART causes rapid recrudescence of HIV plasma viremia due to reactivation of latently HIV-infected cells. Here, we characterize the timing of both the initial and subsequent successful viral reactivations following ART interruption in macaques infected with simian immunodeficiency virus (SIV). We compare these to previous results from HIV-infected patients. We find that on average the time until the first successful viral reactivation event is longer than the time between subsequent reactivations. Based on this result, we hypothesize that the reactivation frequency of both HIV and SIV may fluctuate over time, and that this may impact the treatment of HIV. We develop a stochastic model incorporating fluctuations in the frequency of viral reactivation following ART interruption that shows behaviours consistent with the observed data. Furthermore, we show that one of the impacts of a fluctuating reactivation frequency would be to significantly reduce the efficacy of ‘anti-latency' interventions for HIV that aim to reduce the frequency of reactivation. It is therefore essential to consider the possibility of a fluctuating reactivation frequency when assessing the impact of such intervention strategies.

Consequences of suboptimal priming are apparent for low‐avidity T‐cell responses

Publisher: Wiley

Date: 10-05-2011

DOI: 10.1038/ICB.2011.36

Abstract: The emergence of the novel reassortant A(H1N1)-2009 influenza virus highlighted the threat to the global population posed by an influenza pandemic. Pre-existing CD8(+) T-cell immunity targeting conserved epitopes provides immune protection against newly emerging strains of influenza virus, when minimal antibody immunity exists. However, the occurrence of mutations within T-cell antigenic peptides that enable the virus to evade T-cell recognition constitutes a substantial issue for virus control and vaccine design. Recent evidence suggests that it might be feasible to elicit CD8(+) T-cell memory pools to common virus mutants by pre-emptive vaccination. However, there is a need for a greater understanding of CD8(+) T-cell immunity towards commonly emerging mutants. The present analysis focuses on novel and immunodominant, although of low pMHC-I avidity, CD8(+) T-cell responses directed at the mutant influenza D(b)NP(366) epitope, D(b)NPM6A, following different routes of infection. We used a C57BL/6J model of influenza to dissect the effectiveness of the natural intranasal (i.n.) versus intraperitoneal (i.p.) priming for generating functional CD8(+) T cells towards the D(b)NPM6A epitope. In contrast to comparable CD8(+) T-cell responses directed at the wild-type epitopes, D(b)NP(366) and D(b)PA(224), we found that the priming route greatly affected the numbers, cytokine profiles and TCR repertoire of the responding CD8(+) T cells directed at the D(b)NPM6A viral mutant. As the magnitude, polyfunctionality, and T-cell repertoire ersity are potential determinants of the protective efficacy of CD8(+) T-cell responses, our data have implications for the development of vaccines to combat virus mutants.

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.

Exploration of broadly neutralizing antibody fragments produced in bacteria for the control of HIV

Publisher: Informa UK Limited

Date: 26-09-2017

DOI: 10.1080/21645515.2017.1368935

Is the Gut the Major Source of Virus in Early Simian Immunodeficiency Virus Infection?

Publisher: American Society for Microbiology

Date: 08-2009

DOI: 10.1128/JVI.00552-09

Abstract: The acute phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection are characterized by rapid and profound depletion of CD4 + T cells from the guts of infected in iduals. The large number of CD4 + T cells in the gut (a large fraction of which are activated and express the HIV/SIV coreceptor CCR5), the high level of infection of these cells, and the temporal coincidence of this CD4 + T-cell depletion with the peak of virus in plasma in acute infection suggest that the intestinal mucosa may be the major source of virus driving the peak viral load. Here, we used data on CD4 + T-cell proportions in the lamina propria of the rectums of SIV-infected rhesus macaques (which progress to AIDS) and sooty mangabeys (which do not progress) to show that in both species, the depletion of CD4 + T cells from this mucosal site and its maximum loss rate are often observed several days before the peak in viral load, with few CD4 + T cells remaining in the rectum by the time of peak viral load. In contrast, the maximum loss rate of CD4 + T cells from bronchoalveolar lavage specimens and lymph nodes coincides with the peak in virus. Analysis of the kinetics of depletion suggests that, in both rhesus macaques and sooty mangabeys, CD4 + T cells in the intestinal mucosa are a highly susceptible population for infection but not a major source of plasma virus in acute SIV infection.

Source of CpG Depletion in the HIV-1 Genome

Publisher: Oxford University Press (OUP)

Date: 28-09-2016

DOI: 10.1093/MOLBEV/MSW205

Abstract: The dinucleotide CpG is highly underrepresented in the genome of human immunodeficiency virus type 1 (HIV-1). To identify the source of CpG depletion in the HIV-1 genome, we investigated two biological mechanisms: (1) CpG methylation-induced transcriptional silencing and (2) CpG recognition by Toll-like receptors (TLRs). We hypothesized that HIV-1 has been under selective evolutionary pressure by these mechanisms leading to the reduction of CpG in its genome. A CpG depleted genome would enable HIV-1 to avoid methylation-induced transcriptional silencing and/or to avoid recognition by TLRs that identify foreign CpG sequences. We investigated these two hypotheses by determining the sequence context dependency of CpG depletion and comparing it with that of CpG methylation and TLR recognition. We found that in both human and HIV-1 genomes the CpG motifs flanked by T/A were depleted most and those flanked by C/G were depleted least. Similarly, our analyses of human methylome data revealed that the CpG motifs flanked by T/A were methylated most and those flanked by C/G were methylated least. Given that a similar CpG depletion pattern was observed for the human genome within which CpGs are not likely to be recognized by TLRs, we argue that the main source of CpG depletion in HIV-1 is likely host-induced methylation. Analyses of CpG motifs in over 100 viruses revealed that this unique CpG representation pattern is specific to the human and simian immunodeficiency viruses.

Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries

Publisher: Wiley

Date: 27-09-2017

DOI: 10.1111/HEX.12634

Estimating the in-vivo HIV template switching and recombination rate

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2016

DOI: 10.1097/QAD.0000000000000936

Modeling the dynamics of neonatal CD8⁺ T‐cell responses

Publisher: Wiley

Date: 31-05-2016

DOI: 10.1038/ICB.2016.47

Predicting CD62L expression during the CD8⁺ T‐cell response in vivo

Publisher: Wiley

Date: 27-10-2009

DOI: 10.1038/ICB.2009.80

Fate mapping reveals the age structure of the peripheral T cell compartment

Publisher: Proceedings of the National Academy of Sciences

Date: 14-02-2019

DOI: 10.1073/PNAS.1811634116

Abstract: The development of the peripheral T cell pool is typically described based on the maturation and survival of cells in the periphery, assuming all cells are created equal and have similar lifespans. We have developed a mouse model in which we can “timest ” CD8 + T cells produced at different ages and track their survival. We find that cells produced early in life persist and contribute to the adult pool. However, the dynamics of cell survival are dependent on the age at which they are produced, leading to a shifting population of cells with age. We propose that heterogeneity in the developmental origins of cells contributes to the phenotypic heterogeneity of in idual cells observed in adult animals.

Biological Determinants of Immune Reconstitution in HIV‐Infected Patients Receiving Antiretroviral Therapy: The Role of Interleukin 7 and Interleukin 7 Receptor α and Microbial Translocation

Publisher: Oxford University Press (OUP)

Date: 15-10-2010

DOI: 10.1086/656369

Abstract: Multiple host factors may influence CD4(+) T cell reconstitution in human immunodeficiency virus (HIV)-infected patients after suppressive antiretroviral therapy (ART). We hypothesized that residual immune activation and polymorphisms in the interleukin 7 (IL-7) receptor α (IL-7Rα) gene were important for immune recovery. We examined HIV-infected patients receiving suppressive ART (n = 96) for their IL-7Rα haplotypes and measured levels of lipopolysaccharide (LPS), soluble CD14, and IL-7 in plasma s les collected before and after ART initiation. Levels of soluble IL-7Rα were measured in HIV-infected patients with IL-7Rα haplotype 2 (n = 11) and those without IL-7Rα haplotype 2 (n = 22). Multivariate analysis was used to identify variables associated with faster recovery to CD4(+) T cell counts of >500 and >200 cells/μL. Both LPS and soluble CD14 levels were significantly decreased with ART (P 500 cells/μL was significantly associated with higher baseline CD4(+) T cell count, younger age, lower pre-ART LPS level, higher pre-ART soluble CD14 level, lower pre-ART IL-7 level, and IL-7Rα haplotype 2 (hazard ratio, 1.50 95% confidence interval, 1.03-2.19 P = .034). HIV-infected patients with haplotype 2 had significantly lower soluble IL-7Rα levels compared with those of patients without haplotype 2 (P 500 cells/μL.

Modeling of EBV Infection and Antibody Responses in Kenyan Infants With Different Levels of Malaria Exposure Shows Maternal Antibody Decay is a Major Determinant of Early EBV Infection

Publisher: Oxford University Press (OUP)

Date: 28-08-2016

DOI: 10.1093/INFDIS/JIW396

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

DOI: 10.1371/JOURNAL.PPAT.1005740

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.

Predictors of SIV recrudescence following antiretroviral treatment interruption

Publisher: eLife Sciences Publications, Ltd

Date: 25-10-2019

DOI: 10.7554/ELIFE.49022

Abstract: There is currently a need for proxy measures of the HIV rebound competent reservoir (RCR) that can predict viral rebound after combined antiretroviral treatment (cART) interruption. In this study, macaques infected with a barcoded SIVmac239 virus received cART beginning between 4- and 27 days post-infection, leading to the establishment of different levels of viral dissemination and persistence. Later treatment initiation led to higher SIV DNA levels maintained during treatment, which was significantly associated with an increased frequency of SIV reactivation and production of progeny capable of causing rebound viremia following treatment interruption. However, a 100-fold increase in SIV DNA in PBMCs was associated with only a 2-fold increase in the frequency of reactivation. These data suggest that the RCR can be established soon after infection, and that a large fraction of persistent viral DNA that accumulates after this time makes relatively little contribution to viral rebound.

Predicting the efficacy of variant-modified COVID-19 vaccine boosters

Publisher: Springer Science and Business Media LLC

Date: 03-2023

DOI: 10.1038/S41591-023-02228-4

Low red cell production may protect against severe anemia during a malaria infection—Insights from modeling

Publisher: Elsevier BV

Date: 04-2009

DOI: 10.1016/J.JTBI.2008.12.019

Abstract: The malaria parasite causes lysis of red blood cells, resulting in anemia, a major cause of mortality and morbidity. Intuitively, one would expect the production of red blood cells to increase in order to compensate for this loss. However, it has been observed that this response is weaker than would be expected. Furthermore, iron supplementation for iron deficient children in malaria endemic regions can paradoxically adversely affect the clinical outcome of malaria infection. A possible explanation may lie in the preference that some malaria parasites show for infecting immature red blood cells (reticulocytes). In the presence of a parasite preference for immature red cells, a rise in red cell production can 'fuel the fire' of infection by increasing the availability of the parasite's preferred target cell. We present a mathematical model of red blood cell production and infection in order to explore this hypothesis. We assess the effect of varying the reticulocyte replacement rate and preference of the parasite for reticulocytes on four key outcome measures assessing anemia and parasitemia. For a given level of parasite preference for reticulocytes we uncover an optimal erythropoietic response which minimizes disease severity. Increasing red blood cell production much above this optimum confers no benefit to the patient, and in fact can increase the degree of anemia and parasitemia. These conclusions are consistent with epidemiological studies demonstrating that both iron deficiency and anemia are protective against severe malaria, whilst iron supplementation in malaria endemic regions is with an increased number of malaria related adverse effects. Thus, suppression of red blood cell production, rather than being an unfortunate side effect of inflammation, may be a host protective effect against severe malarial anemia.

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.

Fifteen to twenty percent of HIV substitution mutations are associated with recombination

Publisher: American Society for Microbiology

Date: 04-2014

DOI: 10.1128/JVI.03136-13

Abstract: HIV undergoes high rates of mutation and recombination during reverse transcription, but it is not known whether these events occur independently or are linked mechanistically. Here we used a system of silent marker mutations in HIV and a single round of infection in primary T lymphocytes combined with a high-throughput sequencing and mathematical modeling approach to directly estimate the viral recombination and mutation rates. From million nucleotides (nt) of sequences from HIV infection, we observed 4,801 recombination events and 859 substitution mutations (≈1.51 and 0.12 events per 1,000 nt, respectively). We used experimental controls to account for PCR-induced and transfection-induced recombination and sequencing error. We found that the single-cycle virus-induced mutation rate is 4.6 × 10 −5 mutations per nt after correction. By sorting of our data into recombined and nonrecombined sequences, we found a significantly higher mutation rate in recombined regions ( P = 0.003 by Fisher's exact test). We used a permutation approach to eliminate a number of potential confounding factors and confirm that mutation occurs around the site of recombination and is not simply colocated in the genome. By comparing mutation rates in recombined and nonrecombined regions, we found that recombination-associated mutations account for 15 to 20% of all mutations occurring during reverse transcription.

Intracellular Dynamics of HIV Infection

Publisher: American Society for Microbiology

Date: 15-01-2014

DOI: 10.1128/JVI.02038-13

Abstract: Early studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of in idual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death in vitro . By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death in vivo could be very different, our results suggest that the constant decay of cell numbers observed in vivo during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.

A general method to eliminate laboratory induced recombinants during massive, parallel sequencing of cDNA library

Publisher: Springer Science and Business Media LLC

Date: 09-04-2015

DOI: 10.1186/S12985-015-0280-X

A mechanistic model quantifies artemisinin-induced parasite growth retardation in blood-stage Plasmodium falciparum infection

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.JTBI.2017.07.017

Abstract: Falciparum malaria is a major parasitic disease causing widespread morbidity and mortality globally. Artemisinin derivatives-the most effective and widely-used antimalarials that have helped reduce the burden of malaria by 60% in some areas over the past decade-have recently been found to induce growth retardation of blood-stage Plasmodium falciparum when applied at clinically relevant concentrations. To date, no model has been designed to quantify the growth retardation effect and to predict the influence of this property on in vivo parasite killing. Here we introduce a mechanistic model of parasite growth from the ring to trophozoite stage of the parasite's life cycle, and by modelling the level of staining with an RNA-binding dye, we demonstrate that the model is able to reproduce fluorescence distribution data from in vitro experiments using the laboratory 3D7 strain. We quantify the dependence of growth retardation on drug concentration and identify the concentration threshold above which growth retardation is evident. We estimate that the parasite life cycle is prolonged by up to 10 hours. We illustrate that even such a relatively short delay in growth may significantly influence in vivo parasite dynamics, demonstrating the importance of considering growth retardation in the design of optimal artemisinin-based dosing regimens.

Estimating the Impact of Vaccination on Acute Simian-Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

Publisher: American Society for Microbiology

Date: 12-2008

DOI: 10.1128/JVI.01596-08

Abstract: The dynamics of HIV infection have been studied in humans and in a variety of animal models. The standard model of infection has been used to estimate the basic reproductive ratio of the virus, calculated from the growth rate of virus in acute infection. This method has not been useful in studying the effects of vaccination, since, for the vaccines developed so far, early growth rates of virus do not differ between control and vaccinated animals. Here, we use the standard model of viral dynamics to derive the reproductive ratio from the peak viral load and nadir of target cell numbers in acute infection. We apply this method to data from studies of vaccination in SHIV and SIV infection and demonstrate that vaccination can reduce the reproductive ratio by 2.3- and 2-fold, respectively. This method allows the comparison of vaccination efficacies among different viral strains and animal models in vivo.

Drug-induced thrombocytopenia: Development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG

Publisher: American Society of Hematology

Date: 16-09-2010

DOI: 10.1182/BLOOD-2010-02-268326

Abstract: Drug-induced immune thrombocytopenia (DITP) is an adverse drug effect mediated by drug-dependent antibodies. Intravenous immunoglobulin (IVIG) is frequently used to treat DITP and primary immune thrombocytopenia (ITP). Despite IVIG's proven beneficial effects in ITP, its efficacy in DITP is unclear. We have established a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of DITP in which human platelets survive for more than 24 hours, allowing platelet clearance by DITP/ITP antibodies to be studied. Rapid human platelet clearance was uniformly observed with all quinine-induced thrombocytopenia (QITP) patient sera studied (mean platelet lifespans: QITP 1.5 ± 0.3 hours vs controls 16.5 ± 4.3 hours), consistent with the clinical presentation of DITP. In contrast, clearance rates with ITP antibodies were more variable. IVIG treatment partially prevented platelet clearance by DITP and ITP antibodies. Our results suggest that the NOD/SCID mouse model is useful for investigating the efficacy of current and future DITP therapies, an area in which there is little experimental evidence to guide treatment.

Novel RNA viruses associated with Plasmodium vivax in human malaria and Leucocytozoon parasites in avian disease

Publisher: Public Library of Science (PLoS)

Date: 30-12-2019

DOI: 10.1371/JOURNAL.PPAT.1008216

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.

Correction: 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: 25-08-2016

DOI: 10.1371/JOURNAL.PPAT.1005745

Engagement of a T cell receptor by major histocompatibility complex irrespective of peptide

Publisher: Wiley

Date: 04-1997

DOI: 10.1002/EJI.1830270412

Abstract: T cell receptors (TCR) identify target cells presenting a ligand consisting of a major histocompatibility complex molecule (MHC) and an antigenic peptide. A considerable amount of evidence indicates that the TCR contacts both the peptide and the MHC components of the ligand. In fully differentiated T cells the interaction between the peptide and the TCR makes the critical contribution to eliciting a cellular response. However, during the positive selection of thymocytes the contribution of peptide relative to MHC is less well established. Indeed it has been suggested that the critical interaction for positive selection is between the TCR and the MHC molecule and that peptides can be viewed as either allowing or obstructing this contact. This predicts that a given TCR is capable of engaging multiple MHC eptide complexes. In this study a system is described which detects simply engagement of the TCR by MHC eptide complexes rather than the functional outcome of such interactions. Using this approach the extent to which peptides can influence contacts between the TCR and the MHC molecule has been examined. The results show that the TCR does in fact engage a wide range of ligands in an MHC-restricted but largely peptide-independent manner, suggesting that only a few peptides are able to prevent the TCR from contacting the MHC molecule.

Plasmodium-specific antibodies block in vivo parasite growth without clearing infected red blood cells

Publisher: Public Library of Science (PLoS)

Date: 27-02-2019

DOI: 10.1371/JOURNAL.PPAT.1007599

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.

Use it or lose it: establishment and persistence of T cell memory

Publisher: Frontiers Media SA

Date: 2012

DOI: 10.3389/FIMMU.2012.00357

Infectious diseases: Too little, too late for tuberculosis

Publisher: Wiley

Date: 11-03-2008

DOI: 10.1038/ICB.2008.7

Matryoshka RNA virus 1: a novel RNA virus associated with Plasmodium parasites in human malaria

Publisher: Cold Spring Harbor Laboratory

Date: 05-2019

DOI: 10.1101/624403

Abstract: Parasites of the genus Plasmodium cause human malaria. Yet nothing is known about the viruses that infect these ergent eukaryotes. We investigated the Plasmodium virome by performing a meta-transcriptomic analysis of blood s les from malaria patients infected with P. vivax, P. falciparum or P. knowlesi . This revealed a novel bi-segmented narna-like RNA virus restricted to P. vivax and named Matryoshka RNA virus 1 (MaRNAV-1) to reflect its “Russian doll” nature: a virus, infecting a parasite, infecting an animal. MaRNAV-1 was abundant in geographically erse P. vivax from humans and mosquitoes. Notably, a related virus (MaRNAV-2) was identified in Australian birds infected with a Leucocytozoon - eukaryotic parasites that group with Plasmodium in the Apicomplexa subclass hematozoa. This is the first report of a Plasmodium virus. As well as broadening our understanding of the eukaryotic virosphere, the restriction to P. vivax may help understand P. vivax -specific biology in humans and mosquitoes.

Influence of Peak Viral Load on the Extent of CD4+ T-Cell Depletion in Simian HIV Infection

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2006

DOI: 10.1097/01.QAI.0000199232.31340.D3

Specificity, promiscuity, and precursor frequency in immunoreceptors

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.COI.2013.07.001

Abstract: The immune system is comprised of various immune cell populations that utilize a spectrum of immunoreceptors characterized by different levels of specificity, ersity, and prevalence within a host and across a population. These range from the universal receptors employed by both innate cells and innate-like cells, such as NKT and MAIT cells, through to receptors expressed on T cells with sporadic incidence. Here we review recent advances in understanding the molecular mechanisms that drive the observed spectra of T cell receptors in vivo.

Comparing the Kinetics of NK Cells, CD4, and CD8 T Cells in Murine Cytomegalovirus Infection

Publisher: The American Association of Immunologists

Date: 08-2011

DOI: 10.4049/JIMMUNOL.1100416

Abstract: NK cells recognize virus-infected cells with germline-encoded activating and inhibitory receptors that do not undergo genetic recombination or mutation. Accordingly, NK cells are often considered part of the innate immune response. The innate response comprises rapid early defenders that do not form immune memory. However, there is increasing evidence that experienced NK cells provide increased protection to secondary infection, a hallmark of the adaptive response. In this study, we compare the dynamics of the innate and adaptive immune responses by examining the kinetic profiles of the NK and T cell response to murine CMV infection. We find that, unexpectedly, the kinetics of NK cell proliferation is neither earlier nor faster than the CD4 or CD8 T cell response. Furthermore, early NK cell contraction after the peak of the response is slower than that of T cells. Finally, unlike T cells, experienced NK cells do not experience biphasic decay after the response peak, a trait associated with memory formation. Rather, NK cell contraction is continuous, constant, and returns to below endogenous preinfection levels. This indicates that the reason why Ag-experienced NK cells remain detectable for a prolonged period after adoptive transfer and infection is in part due to the high precursor frequency, slow decay rate, and low background levels of Ly49H+ NK cells in recipient DAP12-deficient mice. Thus, the quantitative contribution of Ag-experienced NK cells in an endogenous secondary response, with higher background levels of Ly49H+ NK cells, may be not be as robust as the secondary response observed in T cells.

Agriculture and digital sustainability: a Digitization Footprint

Publisher: Wageningen Academic Publishers

Date: 08-07-2019

DOI: 10.3920/978-90-8686-888-9_9

SARS-CoV-2 Omicron: evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Publisher: Cold Spring Harbor Laboratory

Date: 15-12-2021

DOI: 10.1101/2021.12.14.21267772

Abstract: Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and / or previously infected in iduals concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise virus in vitro. There was a 17 to 22-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of in iduals infected with the Omicron variant.

CD8+ T Cell Control of HIV—A Known Unknown

Publisher: Public Library of Science (PLoS)

Date: 29-01-2010

DOI: 10.1371/JOURNAL.PPAT.1000728

The molecular basis for public T-cell responses?

Publisher: Springer Science and Business Media LLC

Date: 03-2008

DOI: 10.1038/NRI2260

Abstract: Public T-cell responses, in which T cells bearing identical T-cell receptors (TCRs) are observed to dominate the response to the same antigenic epitope in multiple in iduals, have long been a focus of immune T-cell repertoire studies. However, the mechanism that enables the survival of a specific TCR from the erse repertoire produced in the thymus through to its involvement in a public immune response remains unclear. In this Opinion article, we propose that the frequency of production of T cells bearing different TCRs during recombination has an important role in the sharing of TCRs in an immune response, with variable levels of 'convergent recombination' driving production frequencies.

Stochastic stage-structured modeling of the adaptive immune system

Publisher: IEEE Comput. Soc

Date: 2003

DOI: 10.1109/CSB.2003.1227311

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

DOI: 10.1038/S41591-020-0995-0

The Dynamics of Naturally Acquired Immunity to Plasmodium falciparum Infection

Publisher: Public Library of Science (PLoS)

Date: 18-10-2012

DOI: 10.1371/JOURNAL.PCBI.1002729

Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

Publisher: Public Library of Science (PLoS)

Date: 18-06-2021

DOI: 10.1371/JOURNAL.PPAT.1009686

Abstract: Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track in idual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of in idual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

Escape from highly effective public CD8+ T-cell clonotypes by HIV

Publisher: American Society of Hematology

Date: 25-08-2011

DOI: 10.1182/BLOOD-2011-01-328781

Abstract: Mapping the precise determinants of T-cell efficacy against viruses in humans is a public health priority with crucial implications for vaccine design. To inform this effort, we performed a comprehensive analysis of the effective CD8+ T-cell clonotypes that constitute responses specific for the HIV p24 Gag-derived KK10 epitope (KRWIILGLNK residues 263-272) restricted by HLA-B*2705, which are known to confer superior control of viral replication in HIV-infected in iduals. Particular KK10-specific CD8+ T-cell clonotypes, characterized by TRBV4-3/TRBJ1-3 gene rearrangements, were found to be preferentially selected in vivo and shared between in iduals. These “public” clonotypes exhibit high levels of TCR avidity and Ag sensitivity, which impart functional advantages and enable effective suppression of HIV replication. The early L268M mutation at position 6 of the KK10 epitope enables the virus to avoid recognition by these highly effective CD8+ T-cell clonotypes. However, alternative clonotypes with variant reactivity provide flexibility within the overall KK10-specific response. These findings provide refined mechanistic insights into the workings of an effective CD8+ T-cell response against HIV.

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.

Malaria Parasite Clearance: What Are We Really Measuring?

Publisher: Elsevier BV

Date: 05-2020

DOI: 10.1016/J.PT.2020.02.005

Association of plasma biomarkers of fruit and vegetable intake with incident type 2 diabetes: EPIC-InterAct case-cohort study in eight European countries

Publisher: BMJ

Date: 08-07-2020

DOI: 10.1136/BMJ.M2194

Abstract: To investigate the association of plasma vitamin C and carotenoids, as indicators of fruit and vegetable intake, with the risk of type 2 diabetes. Prospective case-cohort study. Populations from eight European countries. 9754 participants with incident type 2 diabetes, and a subcohort of 13 662 in iduals from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of 340 234 participants: EPIC-InterAct case-cohort study. Incident type 2 diabetes. In a multivariable adjusted model, higher plasma vitamin C was associated with a lower risk of developing type 2 diabetes (hazard ratio per standard deviation 0.82, 95% confidence interval 0.76 to 0.89). A similar inverse association was shown for total carotenoids (hazard ratio per standard deviation 0.75, 0.68 to 0.82). A composite biomarker score (split into five equal groups), comprising vitamin C and in idual carotenoids, was inversely associated with type 2 diabetes with hazard ratios 0.77, 0.66, 0.59, and 0.50 for groups 2-5 compared with group 1 (the lowest group). Self-reported median fruit and vegetable intake was 274 g/day, 396 g/day, and 508 g/day for participants in categories defined by groups 1, 3, and 5 of the composite biomarker score, respectively. One standard deviation difference in the composite biomarker score, equivalent to a 66 (95% confidence interval 61 to 71) g/day difference in total fruit and vegetable intake, was associated with a hazard ratio of 0.75 (0.67 to 0.83). This would be equivalent to an absolute risk reduction of 0.95 per 1000 person years of follow up if achieved across an entire population with the characteristics of the eight European countries included in this analysis. These findings indicate an inverse association between plasma vitamin C, carotenoids, and their composite biomarker score, and incident type 2 diabetes in different European countries. These biomarkers are objective indicators of fruit and vegetable consumption, and suggest that diets rich in even modestly higher fruit and vegetable consumption could help to prevent development of type 2 diabetes.

Reducing chimera formation during PCR amplification to ensure accurate genotyping

Publisher: Elsevier BV

Date: 12-2010

DOI: 10.1016/J.GENE.2010.08.009

Abstract: Measurements of population ersity are fundamental to the reconstruction of the evolutionary and epidemiological history of organisms. Commonly used protocols to measure population ersity using the polymerase chain reaction (PCR) are prone to the introduction of artificial chimeras. These are often difficult to detect and can confound the correct interpretation of results due to the false generation of recombinants when the underlying DNA s le contains multiple distinct templates. This study presents a standardised procedure to suppress the formation of artificial chimeras during PCR lification. The solution is based on the accurate determination of the efficiency and end point of the log-linear phase of a PCR. This procedure will facilitate the generation of data sets that more accurately reflect the underlying population ersity rather than artifacts introduced by the process itself.

Artemisinin-Based Treatments in Pregnant Women with Malaria

Publisher: Massachusetts Medical Society

Date: 21-07-2016

DOI: 10.1056/NEJMC1604709

Timing of Immune Escape Linked to Success or Failure of Vaccination

Publisher: Public Library of Science (PLoS)

Date: 16-09-2010

DOI: 10.1371/JOURNAL.PONE.0012774

Molecular analysis of HLA class II associations with hepatitis B virus clearance and vaccine nonresponsiveness

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2005

DOI: 10.1002/HEP.20716

Abstract: Clearance of acute hepatitis B virus (HBV) infection is associated with a vigorous CD4+ T-cell response focusing on the core protein. HLA class II glycoproteins present viral peptides to CD4+ T cells and influence the immune responses. HLA-DRB1*1301/2 have been associated with viral clearance, and HLA-DRB1*0301 is associated with nonresponse to vaccination with envelope proteins. Binding affinities of overlapping peptides covering the core and envelope proteins of HBV were measured to HLA glycoproteins encoded by HLA-DRA1*0101,-DRB1*0101 (HLA-DR1), HLA-DRA1*0101,-DRB1*0301 (HLA-DR3), HLA-DRA1*0101,-DRB1*0701 (HLA-DR7) and HLA-DRA1*0101,-DRB1*1301 (HLA-DR13) molecules and compared with published peptide-specific CD4+ T-cell responses. There are more high-affinity ligands (IC50 < 1 micromol/L) derived from the core protein than the surface antigen (P < .04 for HLA-DR1/7/13), but there was no increase in the number or the affinity of ligands for HLA-DR13. Clusters of particular core peptides bound to multiple HLA types, explaining the immunodominance of these regions for T-cell responses. Within the envelope protein, the low-affinity ligands (IC50 < 10 micromol/L) are found mainly in the surface antigen, with a marked paucity of ligands for HLA-DR3 (HLA-DR3 vs. non-DR3 P < .05) consistent with the lower vaccination responses for this HLA type. Of all peptides tested, 8 to 10 bound mainly to one HLA type, allowing a substantially greater breadth of response in heterozygotes. In conclusion, these data offer a mechanistic explanation for the dominant response to the HBV core protein during infection and support the direct involvement of the HLA-DRB1 gene in vaccine nonresponsiveness but not altered susceptibility to viral persistence.

Developmental Origin Governs CD8+ T Cell Fate Decisions during Infection

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.CELL.2018.05.029

Abstract: Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8

Diversity and clonotypic composition of influenza‐specific CD8⁺ TCR repertoires remain unaltered in the absence of Aire

Publisher: Wiley

Date: 03-2010

DOI: 10.1002/EJI.200939918

Abstract: TCR repertoire ersity is important for the protective efficacy of CD8(+) T cells, limiting viral escape and cross-reactivity between unrelated epitopes. The exact mechanism for selection of restricted versus erse TCR repertoires is far from clear, although one thought is that the epitopes resembling self-peptides might select a limited array of TCR due to the deletion of autoreactive TCR. The molecule Aire promotes the expression of tissue-specific Ag on thymic medullary epithelial cells and the deletion of autoreactive cells, and in the absence of Aire autoreactive cells persist. However, the contribution of Aire-dependent peptides to the selection of the Ag-specific TCR repertoire remains unknown. In this study, we dissect restricted (D(b)NP(366)%(+)CD8(+)) and erse (D(b)PA(224)%(+)CD8(+), K(d)NP(147)%(+)CD8(+)) TCR repertoires responding to three influenza-derived peptides in Aire-deficient mice on both B6 and BALB/c backgrounds. Our study shows that the number, qualitative characteristics and TCR repertoires of all influenza-specific, D(b)NP(366)%(+)CD8(+), D(b)PA(224)%(+)CD8(+) and K(d)NP(147)%(+)CD8(+) T cells are not significantly altered in the absence of Aire. This provides the first demonstration that the selection of an Ag-specific T-cell repertoire is not significantly perturbed in the absence of Aire.

P09-08. The complexity of the infecting inoculum determines the outcome of infection

Publisher: Springer Science and Business Media LLC

Date: 10-2009

DOI: 10.1186/1742-4690-6-S3-P121

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.

Quantification of host-mediated parasite clearance during blood-stage Plasmodium infection and anti-malarial drug treatment in mice

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.IJPARA.2018.05.010

Abstract: A major mechanism of host-mediated control of blood-stage Plasmodium infection is thought to be removal of parasitized red blood cells (pRBCs) from circulation by the spleen or phagocytic system. The rate of parasite removal is thought to be further increased by anti-malarial drug treatment, contributing to the effectiveness of drug therapy. It is difficult to directly compare pRBC removal rates in the presence and absence of treatment, since in the absence of treatment the removal rate of parasites is obscured by the extent of ongoing parasite proliferation. Here, we transfused a single generation of fluorescently-labelled Plasmodium berghei pRBCs into mice, and monitored both their disappearance from circulation, and their replication to produce the next generation of pRBCs. In conjunction with a new mathematical model, we directly estimated host removal of pRBCs during ongoing infection, and after drug treatment. In untreated mice, pRBCs were removed from circulation with a half-life of 15.1 h. Treatment with various doses of mefloquine/artesunate did not alter the pRBC removal rate, despite blocking parasite replication effectively. An exception was high dose artesunate, which doubled the rate of pRBC removal (half-life of 9.1 h). Phagocyte depletion using clodronate liposomes approximately halved the pRBC removal rate during untreated infection, indicating a role for phagocytes in clearance. We next assessed the importance of pRBC clearance for the decrease in the parasite multiplication rate after high dose artesunate treatment. High dose artesunate decreased parasite replication ∼46-fold compared with saline controls, with inhibition of replication contributing 23-fold of this, and increased pRBC clearance contributing only a further 2.0-fold. Thus, in our in vivo systems, drugs acted primarily by inhibiting parasite replication, with drug-induced increases in pRBC clearance making only minor contributions to overall drug effect.

Acute Neonatal Infections ‘Lock-In’ a Suboptimal CD8+ T Cell Repertoire with Impaired Recall Responses

Publisher: Public Library of Science (PLoS)

Date: 12-09-2013

DOI: 10.1371/JOURNAL.PPAT.1003572

APOBEC3 has not left an evolutionary footprint on the HIV-1 genome

Publisher: American Society for Microbiology

Date: 09-2011

DOI: 10.1128/JVI.00658-11

Abstract: It is known that the human immune proteins APOBEC3G and -F (hA3G/F) can inhibit Vif-deficient HIV by G-to-A mutation however, the roles of these enzymes in the evolution of HIV are debated. We argue that if evolutionary pressure from hA3G/F exists there should be evidence of their imprint on the HIV genome in the form of (i) underrepresentation of hA3G/F target motifs (e.g., T G GG [targeted position is underlined]) and overrepresentation of product motifs (e.g., T A GG) and/or (ii) an increase in the ratio of nonsynonymous to synonymous (NS/S) G-to-A changes among hA3G/F target motifs and a decrease of NS/S A-to-G changes among hA3G/F product motifs. To test the first hypothesis, we studied the representation of hA3G/F target and product motifs in 1,932 complete HIV-1 genomes using Markov models. We found that the highly targeted motifs are not underrepresented and their product motifs are not overrepresented. To test the second hypothesis, we determined the NS/S G↔A changes among the hA3G/F target and product motifs in 1,540 complete sets of nine HIV-1 genes. The NS/S changes did not show an increasing/decreasing trend within the target roduct motifs, but the NS/S changes within the motif A G was exceptionally low. We observed the same pattern by analyzing 740 human genes. Given that hA3G/F do not act on the human genome, this suggests a small NS/S change within A G has arisen by other mechanisms. We therefore find no evidence of an evolutionary footprint of hA3G/F. We postulate several mechanisms to explain why the HIV-1 genome does not contain the hA3G/F footprint.

Evolution of the Antigen-Specific CD8+ TCR Repertoire across the Life Span: Evidence for Clonal Homogenization of the Old TCR Repertoire

Publisher: The American Association of Immunologists

Date: 15-02-2011

DOI: 10.4049/JIMMUNOL.1003013

Abstract: Defects in T cell responses against pathogens and reduced ersity of TCRs have been described at both extremes of the life span. Yet, we still lack information on how Ag-specific T cell populations are maintained and/or altered from birth to old age. In this study, for the first time to our knowledge, we provide insight into Ag-specific TCR repertoire changes over the life span at the single-cell level. We have examined the TCR ersity of the primary CD8+ T cell response to the immunodominant HSV-1 epitope HSV glycoprotein B 495–502 (HSV gB498–505 SSIEFARL) (gB-8p) in neonatal, adult, and old C57BL/6 mice. The global distinctive features of the gB-8p–specific TCR repertoire were preserved in mice of different ages. However, both old and especially neonatal mice exhibited significant decreases in TCR ersity compared with that of adult mice. Still, although the neonatal Ag-specific repertoire comprised expectedly shorter germline-biased CDR3β lengths, the repertoire was surprisingly complex, and only a minority of responding cells lacked random nucleotide additions. Changes with aging included increased use of the already dominant TCRVβ10 family, a trend for lower content of the TCR containing the germline WG motif in the CDR3, and a remarkable sharing of one dominant clonotype between in idual old mice, implying operation of selective mechanisms. Implications for the rational design of vaccines for neonates and the elderly are discussed.

CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages

Publisher: Elsevier BV

Date: 11-2014

DOI: 10.1016/J.CELREP.2014.09.045

Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus

Publisher: American Society for Microbiology

Date: 15-10-2004

DOI: 10.1128/JVI.78.20.11340-11351.2004

Abstract: Studies of human immunodeficiency virus (HIV) vaccines in animal models suggest that it is difficult to induce complete protection from infection (sterilizing immunity) but that it is possible to reduce the viral load and to slow or prevent disease progression following infection. We have developed an age-structured epidemiological model of the effects of a disease-modifying HIV vaccine that incorporates the intrahost dynamics of infection, a transmission rate and host mortality that depend on the viral load, the possible evolution and transmission of vaccine escape mutant viruses, a finite duration of vaccine protection, and possible changes in sexual behavior. Using this model, we investigated the long-term outcome of a disease-modifying vaccine and utilized uncertainty analysis to quantify the effects of our lack of precise knowledge of various parameters. Our results suggest that the extent of viral load reduction in vaccinated infected in iduals (compared to unvaccinated in iduals) is the key predictor of vaccine efficacy. Reductions in viral load of about 1 log 10 copies ml −1 would be sufficient to significantly reduce HIV-associated mortality in the first 20 years after the introduction of vaccination. Changes in sexual risk behavior also had a strong impact on the epidemic outcome. The impact of vaccination is dependent on the population in which it is used, with disease-modifying vaccines predicted to have the most impact in areas of low prevalence and rapid epidemic growth. Surprisingly, the extent to which vaccination alters disease progression, the rate of generation of escape mutants, and the transmission of escape mutants are predicted to have only a weak impact on the epidemic outcome over the first 25 years after the introduction of a vaccine.

Decreased Growth Rate of P. falciparum Blood Stage Parasitemia With Age in a Holoendemic Population

Publisher: Oxford University Press (OUP)

Date: 21-11-2013

DOI: 10.1093/INFDIS/JIT613

Validation of RNA-based molecular clonotype analysis for virus-specific CD8+ T-cells in formaldehyde-fixed specimens isolated from peripheral blood

Publisher: Elsevier BV

Date: 09-2007

DOI: 10.1016/J.JIM.2007.07.016

Interaction between maternally derived antibodies and heterogeneity in exposure combined to determine time-to-first Plasmodium falciparum infection in Kenyan infants

Publisher: Springer Science and Business Media LLC

Date: 22-01-2019

DOI: 10.1186/S12936-019-2657-6

A meta-analysis of Early Results to predict Vaccine efficacy against Omicron

Publisher: Cold Spring Harbor Laboratory

Date: 14-12-2021

DOI: 10.1101/2021.12.13.21267748

Abstract: In the studies to date, the estimated fold-drop in neutralisation titre against Omicron ranges from 2- to over 20-fold depending on the study and serum tested. Collating data from the first four of these studies results in a combined estimate of the drop in neutralisation titre against Omicron of 9.7-fold (95% CI 5.5-17.1). We use our previously established model to predict that six months after primary immunisation with an mRNA vaccine, efficacy for Omicron is estimated to have waned to around 40% against symptomatic and 80% against severe disease. A booster dose with an existing mRNA vaccine (even though it targets the ancestral spike) has the potential to raise efficacy for Omicron to 86.2% (95% CI: 72.6-94) against symptomatic infection and 98.2% (95% CI: 90.2-99.7) against severe infection.

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

Molecularly barcoded Zika virus libraries to probe in vivo evolutionary dynamics

Publisher: Public Library of Science (PLoS)

Date: 28-03-2018

DOI: 10.1371/JOURNAL.PPAT.1006964

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.

Naïve and Memory Cell Turnover as Drivers of CCR5-to-CXCR4 Tropism Switch in Human Immunodeficiency Virus Type 1: Implications for Therapy

Publisher: American Society for Microbiology

Date: 15-01-2006

DOI: 10.1128/JVI.80.2.802-809.2006

Abstract: Early human immunodeficiency virus infection is characterized by the predominance of CCR5-tropic (R5) virus. However, in many in iduals CXCR4-tropic (X4) virus appears in late infection. The reasons for this phenotypic switch are unclear. The patterns of chemokine receptor expression suggest that X4 and R5 viruses have a preferential tropism for naïve and memory T cells, respectively. Since memory cells ide approximately 10 times as often as naïve cells in uninfected in iduals, a tropism for memory cells in early infection may provide an advantage. However, with disease progression both naïve and memory cell ision frequencies increase, and at low CD4 counts, the naïve cell ision frequency approaches that of memory cells. This may provide a basis for the phenotypic switch from R5 to X4 virus observed in late infection. We show that a model of infection using observed values for cell turnover supports this mechanism. The phenotypic switch from R5 to X4 virus occurs at low CD4 counts and is accompanied by a rapid rise in viral load and drop in CD4 count. Thus, low CD4 counts are both a cause and an effect of X4 virus dominance. We also investigate the effects of different antiviral strategies. Surprisingly, these results suggest that both conventional antiretroviral regimens and CCR5 receptor-blocking drugs will promote R5 virus over X4 virus.

Tentative first steps to eradicate latent HIV

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/S2352-3018(14)70015-3

A virus-specific CD8+ T cell immunodominance hierarchy determined by antigen dose and precursor frequencies.

Publisher: Proceedings of the National Academy of Sciences

Date: 17-01-2006

DOI: 10.1073/PNAS.0510429103

Abstract: Immunodominance hierarchies are a substantial, but poorly understood, characteristic of CD8 + T cell-mediated immunity. Factors influencing the differential responses to the influenza A virus nucleoprotein (NP 366–374 ) and acid polymerase (PA 224–233 ) peptides presented by H2D b have been analyzed by disabling (N5→ Q substitution) these peptides in their native configuration, then expressing them in the viral neuraminidase protein. This strategy of shifting epitopes within the same viral context resulted in an apparent equalization of D b NP 366 [epitope consisting of viral nucleoprotein (NP) amino acid residues 366–374 complexed with the H2D b MHC class I glycoprotein] and D b PA 224 (H2D b +PA 224–233 ) epitope abundance after direct infection in vitro and induced reproducible changes in the magnitude of the D b NP 366 - and D b PA 224 -specific T cell subsets generated after infection of mice. Comparison of D b NP 366 - and D b PA 224 -specific CD8 + T cell responses induced from the native configuration and from the viral neuraminidase stalk demonstrated that the size of both primary and secondary responses is influenced by relative epitope levels and that, at least after secondary challenge, the magnitude of responses is also determined by CD8 + T cell precursor frequency. Thus, this immunodominance hierarchy is a direct function of antigen dose and T cell numbers.

Defining the Effectiveness of Antimalarial Chemotherapy: Investigation of the Lag in Parasite Clearance Following Drug Administration

Publisher: Oxford University Press (OUP)

Date: 31-05-2016

DOI: 10.1093/INFDIS/JIW234

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Publisher: American Society for Microbiology

Date: 15-05-2014

DOI: 10.1128/JVI.00017-14

Abstract: The mechanisms of increased memory CD4 + T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and Vβ family distribution in cycling memory CD4 + T cells among 52 healthy and 59 HIV-positive (HIV + ) donors. Cycling memory CD4 + T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4 + T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV + donors, memory CD4 + T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8 + T cell cycling and was inversely related to peripheral blood CD4 + T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4 + T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV + donors, cycling memory CD4 + T cells had a broad distribution of Vβ families comparable to that of noncycling cells. Increased memory CD4 + T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines. IMPORTANCE This work provides evidence that the increased memory CD4 + T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection.

The promiscuous B27 hypothesis

Publisher: Elsevier BV

Date: 08-1995

DOI: 10.1016/S0140-6736(95)91348-3

Modelling the impact of antigen kinetics on T‐cell activation and response

Publisher: Wiley

Date: 02-2004

DOI: 10.1111/J.1440-1711.2004.01207.X

Abstract: Cytotoxic T lymphocyte (CTL) responses are thought to be important for the control of many viral and other infections. Qualitative aspects of the CTL response, including the epitope specificity, affinity, and clonal composition, may affect the ability of T cells to mediate infection control. Although it is clear that the mode of introduction and the dose of antigen can affect these qualitative aspects of the response, little is understood of the mechanisms. We have developed an in silico model of the CTL response, which we use to study the impact of antigen dose, antigen kinetics and repeated antigen delivery on the response. The results suggest that recent observations on differences in response to killed antigen can be explained simply by differences in timing of T-cell activation. These findings may provide insight into how different vaccination strategies can quantitatively and qualitatively affect the outcome of the immune response.

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.

DNAzyme targeting c-jun suppresses skin cancer growth

Publisher: American Association for the Advancement of Science (AAAS)

Date: 20-06-2012

DOI: 10.1126/SCITRANSLMED.3003960

Abstract: Catalytic DNA molecules that target the transcription factor c- jun inhibit skin cancer growth in mice.

The race between infection and immunity: how do pathogens set the pace?

Publisher: Elsevier BV

Date: 02-2009

DOI: 10.1016/J.IT.2008.11.001

Abstract: Infection is often referred to as a race between pathogen and immune response. This metaphor suggests that slower growing pathogens should be more easily controlled. However, a growing body of evidence shows that many chronic infections are caused by failure to control slow growing pathogens. The slow growth of pathogens seems to directly affect the kinetics of the immune response. Compared with the response to fast growing pathogens, the T-cell response to slow pathogens is delayed in its initiation, lymphocyte expansion is slow and the response often fails to clear the pathogen, leading to chronic infection. Understanding the 'rules of the race' for slow growing pathogens has important implications for vaccine design and immune control of many chronic infections.

Metagenomic analysis of the impact of nitrofurantoin treatment on the human faecal microbiota

Publisher: Oxford University Press (OUP)

Date: 12-03-2015

DOI: 10.1093/JAC/DKV062

Abstract: The objective was to study changes in the faecal microbiota of patients with uncomplicated urinary tract infections (UTIs) treated with nitrofurantoin and of non-treated healthy controls using 16S rRNA analysis. Serial stool s les were collected from patients receiving nitrofurantoin treatment at different timepoints [before treatment (day 1 T1), within 48 h of end of treatment (days 5–15 T2) and 28 days after treatment (days 31–43 T3)], as well as from healthy controls. Direct DNA extraction (PowerSoil DNA Isolation Kit, MoBio Laboratories, Carlsbad, CA, USA) from stool s les was followed by pyrosequencing (454 GS FLX Titanium) of the V3–V5 region of the bacterial 16S rRNA gene. Among UTI patients, mean proportions of the Actinobacteria phylum increased by 19.6% in the first follow-up s le (T2) in comparison with the pretreatment baseline stool s le (T1) (P = 0.026). However, proportions of Actinobacteria reversed to ‘normal’ pre-antibiotic levels, with a mean difference of 1.0% compared with baseline proportions, in the second follow-up s le (T3). The increase in Actinobacteria was specifically due to an increase in the Bifidobacteriaceae family (Bifidobacterium genus), which constituted 81.0% (95% CI ±7.4%) of this phylum. No significant impact was observed other than a temporary increase in the beneficial Bifidobacterium genus following nitrofurantoin treatment, which supports its reintroduction into clinical use.

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

Publisher: American Society for Microbiology

Date: 2014

DOI: 10.1128/IAI.00705-13

Abstract: Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum -infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection.

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.

The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection

Publisher: The American Association of Immunologists

Date: 15-02-2016

DOI: 10.4049/JIMMUNOL.1501867

Abstract: CMV is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. Previous reports have shown that CD8+ T cells are required to control viral replication and significant numbers of CMV-specific CD8+ T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8+ T cells in the brain during latency remain largely undefined. In this report, we used TCR sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue-resident memory CD8+ T cells, we hypothesized that neonatal TCR clonotypes would be locked in the brain and persist into adulthood. Surprisingly, we found that the Ag-specific T cell repertoire in neonatal-infected mice ersified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8+ T cell populations in the brain and spleen in both early and late infection. However, despite the ersification of, and potential interchange between, the spleen and brain Ag-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8+ T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.

Parasite viability is a superior measure of anti-malarial drug activity in humans.

Publisher: Oxford University Press (OUP)

Date: 29-10-2020

DOI: 10.1093/INFDIS/JIAA678

Abstract: Artemisinin derivatives are the leading class of antimalarial drugs due to their rapid onset of action and rapid clearance of circulating parasites. The parasite clearance half-life measures the rate of loss of parasites from blood after treatment, and this is currently used to assess antimalarial activity of novel agents and to monitor resistance. However, a number of recent studies have challenged the use of parasite clearance to measure drug activity, arguing that many circulating parasites may be nonviable. Plasmodium falciparum–infected subjects (n = 10) in a malaria volunteer infection study were administered a single dose of artesunate (2 mg/kg). Circulating parasite concentration was assessed by means of quantitative polymerase chain reaction (qPCR). Parasite viability after artesunate administration was estimated by mathematical modeling of the ex vivo growth of parasites collected from subjects. We showed that in artemisinin-sensitive infection, viable parasites declined to & .1% of baseline within 8 hours after artesunate administration, while the total number of circulating parasites measured with quantitative polymerase chain reaction remained unchanged. In artemisinin-resistant infections over the same interval, viable parasites declined to 51.4% (standard error of the mean, 4.6%) of baseline. These results demonstrate that in vivo drug activity of artesunate is faster than is indicated by the parasite clearance half-life.

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.

Nonrandom attrition of the naive CD8 ⁺ T-cell pool with aging governed by T-cell receptor:pMHC interactions

Publisher: Proceedings of the National Academy of Sciences

Date: 03-08-2011

DOI: 10.1073/PNAS.1107594108

Abstract: Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and ersity of naive CD8 + T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired “memory-like” phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and ersity defects in old T cells.

The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8+ TCRs between Macaques

Publisher: The American Association of Immunologists

Date: 15-08-2008

DOI: 10.4049/JIMMUNOL.181.4.2597

Abstract: In some epitope-specific responses, T cells bearing identical TCRs occur in many MHC-matched in iduals. The sharing of public TCRs is unexpected, given the enormous potential ersity of the TCR repertoire. We have previously studied the sharing of TCR β-chains in the CD8+ T cell responses to two influenza epitopes in mice. Analysis of these TCRβ repertoires suggests that, even with unbiased V(D)J recombination mechanisms, some TCRβs can be produced more frequently than others, by a process of convergent recombination. The TCRβ production frequency was shown to be a good predictor of the observed sharing of epitope-specific TCRβs between mice. However, this study was limited to immune responses in an inbred population. In this study, we investigated TCRβ sharing in CD8+ T cell responses specific for the immunodominant Mamu-A*01-restricted Tat-SL8/TL8 and Gag-CM9 epitopes of SIV in rhesus macaques. Multiple data sets were used, comprising a total of ∼6000 TCRβs s led from 20 macaques. We observed a spectrum in the number of macaques sharing epitope-specific TCRβs in this outbred population. This spectrum of TCRβ sharing was negatively correlated with the minimum number of nucleotide additions required to produce the sequences and strongly positively correlated with the number of observed nucleotide sequences encoding the amino acid sequences. We also found that TCRβ sharing was correlated with the number of times, and the variety of different ways, the sequences were produced in silico via random gene recombination. Thus, convergent recombination is a major determinant of the extent of TCRβ sharing.

Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

Publisher: Public Library of Science (PLoS)

Date: 08-12-2016

DOI: 10.1371/JOURNAL.PNTD.0005139

Durable reprogramming of neutralizing antibody responses following Omicron breakthrough infection

Publisher: American Association for the Advancement of Science (AAAS)

Date: 21-07-2023

DOI: 10.1126/SCIADV.ADG5301

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.

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.

IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection

Publisher: American Society for Clinical Investigation

Date: 20-06-2016

DOI: 10.1172/JCI85996

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.

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.

Building a T cell compartment: how immune cell development shapes function

Publisher: Springer Science and Business Media LLC

Date: 03-06-2020

DOI: 10.1038/S41577-020-0332-3

Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection

Publisher: Rockefeller University Press

Date: 06-04-2009

DOI: 10.1084/JEM.20081127

Abstract: Despite the pressing need for an AIDS vaccine, the determinants of protective immunity to HIV remain concealed within the complexity of adaptive immune responses. We dissected immunodominant virus-specific CD8+ T cell populations in Mamu-A*01+ rhesus macaques with primary SIV infection to elucidate the hallmarks of effective immunity at the level of in idual constituent clonotypes, which were identified according to the expression of distinct T cell receptors (TCRs). The number of public clonotypes, defined as those that expressed identical TCR β-chain amino acid sequences and recurred in multiple in iduals, contained within the acute phase CD8+ T cell population specific for the biologically constrained Gag CM9 (CTPYDINQM residues 181–189) epitope correlated negatively with the virus load set point. This independent molecular signature of protection was confirmed in a prospective vaccine trial, in which clonotype engagement was governed by the nature of the antigen rather than the context of exposure and public clonotype usage was associated with enhanced recognition of epitope variants. Thus, the pattern of antigen-specific clonotype recruitment within a protective CD8+ T cell population is a prognostic indicator of vaccine efficacy and biological outcome in an AIDS virus infection.

Similarly efficacious anti-malarial drugs SJ733 and pyronaridine differ in their ability to remove circulating parasites in mice

Publisher: Springer Science and Business Media LLC

Date: 16-02-2022

DOI: 10.1186/S12936-022-04075-Z

Abstract: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the “parasite clearance curve”, has been critical for assessing drug efficacy yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation. In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound’s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication. These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal. Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites.

Symptomatic and Asymptomatic Viral Recrudescence in Solid-Organ Transplant Recipients and Its Relationship with the Antigen-Specific CD8 ⁺ T-Cell Response

Publisher: American Society for Microbiology

Date: 15-10-2007

DOI: 10.1128/JVI.00581-07

Abstract: Using ex vivo antigen-specific T-cell analysis, we found that symptomatic cytomegalovirus recrudescence in transplant recipients was coincident with reduced expression of gamma interferon (IFN-γ) by virus-specific CD8 + T cells and an up-regulation of CD38 expression on these T cells, although there was no significant change in the absolute number of virus-specific cells (as assessed by major histocompatibility complex-peptide multimers). In contrast, HLA class I-matched transplant patients with asymptomatic viral recrudescence showed increased expansion of antigen-specific T cells and highly stable IFN-γ expression by epitope-specific T cells. These studies suggest that a strong functional T-cell response plays a crucial role in defining the clinical outcome of acute viral recrudescence.

HIV Reactivation after Partial Protection by Neutralizing Antibodies

Publisher: Elsevier BV

Date: 05-2018

DOI: 10.1016/J.IT.2017.12.006

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.

Accurately Measuring Recombination between Closely Related HIV-1 Genomes

Publisher: Public Library of Science (PLoS)

Date: 29-04-2010

DOI: 10.1371/JOURNAL.PCBI.1000766

Developing a Tool for Auditing the Quality of Antibiotic Dispensing in Community Pharmacies: A Pilot Study

Publisher: MDPI AG

Date: 11-2022

DOI: 10.3390/ANTIBIOTICS11111529

Abstract: Background: The European Centre for Disease Prevention and Control describes the community pharmacist as the gatekeeper to the quality of antibiotic use. The pharmacist has the responsibility to guard safe and effective antibiotic use however, little is known about how this is implemented in practice. Aims: To assess the feasibility of a method to audit the quality of antibiotic dispensing in community pharmacy practice and to explore antibiotic dispensing practices in Greece, Lithuania, Poland, and Spain. Methods: The Audit Project Odense methodology to audit antibiotic dispensing practice was adapted for use in community pharmacy practice. Community pharmacists registered antibiotic dispensing on a specifically developed registration chart and were asked to provide feedback on the registration method. Results: Altogether, twenty pharmacists were recruited in four countries. They registered a total of 409 dispenses of oral antibiotics. Generally, pharmacists were positive about the feasibility of implementing the registration chart in practice. The frequency of checking for allergies, contraindications and interactions differed largely between the four countries. Pharmacists provided little advice to patients. The pharmacists rarely contacted prescribers. Conclusion: This tool seems to make it possible to get a useful picture of antibiotic dispensing patterns in community pharmacies. Dispensing practice does not seem to correspond with EU guidelines according to these preliminary results.

Immunogenetics and transplantation

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.COI.2013.09.001

Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine

Publisher: Cold Spring Harbor Laboratory

Date: 22-02-2022

DOI: 10.1101/2022.02.20.481163

Abstract: Despite a clear role in protective immunity, the durability and quality of antibody and memory B cell responses induced by mRNA vaccination, particularly by a 3 rd dose of vaccine, remains unclear. Here, we examined antibody and memory B cell responses in a cohort of in iduals s led longitudinally for ∼9-10 months after the primary 2-dose mRNA vaccine series, as well as for ∼3 months after a 3 rd mRNA vaccine dose. Notably, antibody decay slowed significantly between 6- and 9-months post-primary vaccination, essentially stabilizing at the time of the 3 rd dose. Antibody quality also continued to improve for at least 9 months after primary 2-dose vaccination. Spike- and RBD-specific memory B cells were stable through 9 months post-vaccination with no evidence of decline over time, and ∼40-50% of RBD-specific memory B cells were capable of simultaneously recognizing the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells induced by the first 2 doses of mRNA vaccine were boosted significantly by a 3rd dose and the magnitude of this boosting was similar to memory B cells specific for other variants. Pre-3 rd dose memory B cell frequencies correlated with the increase in neutralizing antibody titers after the 3 rd dose. In contrast, pre-3 rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit reactivation of immunological memory and constrain further antibody boosting by mRNA vaccines. These data provide a deeper understanding of how the quantity and quality of antibody and memory B cell responses change over time and number of antigen exposures. These data also provide insight into potential immune dynamics following recall responses to additional vaccine doses or post-vaccination infections.

Early microbial exposure shapes adult immunity by altering CD8+ T cell development.

Publisher: Proceedings of the National Academy of Sciences

Date: 28-11-2022

DOI: 10.1073/PNAS.2212548119

Abstract: Microbial exposure during development can elicit long-lasting effects on the health of an in idual. However, how microbial exposure in early life leads to permanent changes in the immune system is unknown. Here, we show that the microbial environment alters the set point for immune susceptibility by altering the developmental architecture of the CD8+ T cell compartment. In particular, early microbial exposure results in the preferential expansion of highly responsive fetal-derived CD8+ T cells that persist into adulthood and provide the host with enhanced immune protection against intracellular pathogens. Interestingly, microbial education of fetal-derived CD8+ T cells occurs during thymic development rather than in the periphery and involves the acquisition of a more effector-like epigenetic program. Collectively, our results provide a conceptual framework for understanding how microbial colonization in early life leads to lifelong changes in the immune system.

Estimating cytomegalovirus growth rates by using only a single point

Publisher: American Society for Microbiology

Date: 15-03-2013

DOI: 10.1128/JVI.02821-12

Abstract: Calculation of pathogen growth rates is important in understanding the natural history of infection and effects of therapy. However, it is often difficult to estimate pathogen growth because patients are treated immediately upon the detection of infection, leaving only one nonzero untreated reading. Previous approaches have relied on the flawed assumption that pathogen loads just prior to detection are at the assay detection threshold. We have developed a novel method for estimating the pathogen growth rate from a single reading and investigated the initial growth of cytomegalovirus (CMV) in allogeneic hematopoietic stem cell transplant (HSCT) patients. We applied this approach to CMV viral loads measured at least weekly in 122 patients in the 3 months posttransplant. Viral growth rates were estimated by using a modeling approach that accounts for the viral load and the time since the last negative reading. Viral growth rates decreased rapidly within the first week, from 0.72/day (doubling time, 0.96 day) at the point of reactivation to 0.22/day (doubling time, 3.1 days) at 1 week. Results from this method correlated closely with a two-point regression analysis of a subset of 58 patients with detectable subthreshold viral loads immediately prior to overt reactivation. Patients with lymphocyte counts of ≥0.5 × 10 9 /liter had significantly slower viral growth than patients with low lymphocyte counts (0.612/day versus 0.325/day, P 0.0001). Thus, our novel method of estimating pathogen growth rates reveals a rapid slowing of CMV growth during reactivation in HSCT patients and a significant impact of the lymphocyte count on CMV growth.

Methods for comparing the diversity of samples of the T cell receptor repertoire

Publisher: Elsevier BV

Date: 04-2007

DOI: 10.1016/J.JIM.2007.01.019

Abstract: Analysis of T cell receptor (TCR) data has become a crucial element in many studies aimed at better understanding the evolution of the T cell repertoire and the role of TCR ersity in immune responses. In this paper we focus on comparing the ersity between s les of the TCR repertoire. We discuss some of the limitations and potential problems inherent in some of the more popular approaches to comparing s les of the TCR repertoire and we suggest alternate methods that both avoid these problems and enrich the analysis of TCR data. Ex les from published studies of the CD8(+) T cell responses to the influenza A virus D(b)NP(366) and D(b)PA(224) epitopes in mice are used to demonstrate the implementation of these methods. One ex le involves a comparison between the central and effector memory T cell subsets, defined on the basis of CD62L expression, and the other examines changes in the TCR repertoire over time.

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

DOI: 10.1038/S41577-022-00716-1

Sequential Broadening of CTL Responses in Early HIV-1 Infection Is Associated with Viral Escape

Publisher: Public Library of Science (PLoS)

Date: 21-02-2007

DOI: 10.1371/JOURNAL.PONE.0000225

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

DOI: 10.1371/JOURNAL.PONE.0093330

Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression

Publisher: Springer Science and Business Media LLC

Date: 26-06-2011

DOI: 10.1038/NM.2395

Reduced erythrocyte susceptibility and increased host clearance of young parasites slows Plasmodium growth in a murine model of severe malaria

Publisher: Springer Science and Business Media LLC

Date: 06-05-2015

DOI: 10.1038/SREP09412

Abstract: The best correlate of malaria severity in human Plasmodium falciparum ( Pf ) infection is the total parasite load. Pf- infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo . Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients and tracked the fate of donor parasites by frequent blood s ling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.

Early establishment of diverse T cell receptor profiles for influenza-specific CD8 ⁺ CD62L ^hi memory T cells

Publisher: Proceedings of the National Academy of Sciences

Date: 13-06-2006

DOI: 10.1073/PNAS.0603289103

Abstract: Single-cell analysis of endogenous, primary CD8 + T cell responses to the influenza D b NP 366 and D b PA 224 epitopes indicates that prominent clonotypes bearing “public” or “shared” T cell receptors (TCRs) subset early into CD62L hi and CD62L lo populations. The CD62L lo effectors ide more and are rapidly eliminated during the contraction phase, whereas stable CD62L hi memory populations persist in the long-term. Reflecting the high frequency of small CD62L hi clones expressing “private” TCRs, the TCR ersity range per mouse is generally two times higher within the CD62L hi CD8 + D b NP 366 + set (1.6 times higher for CD62L hi CD8 + D b PA 224 + ) from 8 to days after antigen challenge. Memory CD8 + CD62L hi T cell precursors thus segregate from the outset into populations expressing “best-fit” and “suboptimal” TCR characteristics, with this pattern being maintained stably thereafter. Hence, our analysis suggests that early establishment of influenza-specific memory within the CD8 + CD62L hi subset preserves clonal ersity and prevents “overdominance” by a few public, or shared, clones.

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.

Lifelong Persistent Viral Infection Alters the Naive T Cell Pool, Impairing CD8 T Cell Immunity in Late Life

Publisher: The American Association of Immunologists

Date: 12-2012

DOI: 10.4049/JIMMUNOL.1201867

Abstract: Persistent CMV infection has been associated with immune senescence. To address the causal impact of lifelong persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, murine CMV, or both viruses and studied their T cell homeostasis and function. Herpesvirus+ mice exhibited increased all-cause mortality compared with controls. Upon Listeria-OVA infection, 23-mo-old animals that had experienced lifelong herpesvirus infections showed impaired bacterial control and CD8 T cell function, along with distinct alterations in the T cell repertoire both before and after Listeria challenge, compared with age-matched, herpesvirus-free controls. Herpesvirus infection was associated with reduced naive CD8 T cell precursors above the loss attributable to aging. Moreover, the OVA-specific CD8 T cell repertoire recruited after Listeria challenge was entirely nonoverlapping between control and herpesvirus+ mice. To our knowledge, this study for the first time causally links lifelong herpesvirus infection to all-cause mortality in mice and to disturbances in the T cell repertoire, which themselves correspond to impaired immunity to a new infection in aging.

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.

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

DOI: 10.1371/JOURNAL.PPAT.1002615

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.

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial

Publisher: Cold Spring Harbor Laboratory

Date: 30-06-2021

DOI: 10.1101/2021.06.29.21259504

Abstract: A recent study analysed the relationship between neutralising antibody response and protection from SARS-CoV-2 infection across eight vaccine platforms 1 . The efficacy results from a phase 2b/3 trial of a ninth vaccine candidate, CVnCoV (CUREVAC), was announced on 16 June 2021 2 . The low efficacy of this new mRNA vaccine, which showed only 47% protection from symptomatic SARS-CoV-2 infection, was surprising given the high efficacy of two previous mRNA-based vaccines 3,4 . A number of factors have been suggested to play a role in the low efficacy in the CVnCoV study, particularly around the dose and immunogenicity of the vaccine (which uses an unmodified mRNA construct 5,6 ) and the potential role of infection with SARS-CoV-2 variants (which were the dominant strains observed in the CVnCoV trial) 2 .

CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

Publisher: American Society for Clinical Investigation

Date: 15-04-2021

DOI: 10.1172/JCI141677

Estimating the Infectivity of CCR5-Tropic Simian Immunodeficiency Virus SIV _mac251 in the Gut

Publisher: American Society for Microbiology

Date: 08-2007

DOI: 10.1128/JVI.01771-06

Abstract: CD4 + T-cell depletion during acute human immunodeficiency virus infection occurs predominantly in the gastrointestinal mucosa. Using experimental data on SIV mac251 viral load in blood and CD4 + T cells in the jejunum, we modeled the kinetics of CD4 + T-cell infection and death and estimated the viral infectivity. The infectivity of SIV mac251 is higher than previously estimated for SHIV89.6P infection, but this higher infectivity is offset by a lower average peak viral load in SIV mac251 . Thus, the dynamics of target cell infection and death are remarkably similar between a CXCR4- and a CCR5-tropic infection in vivo.

HIV Immune Escape at an Immunodominant Epitope in HLA-B*27–Positive Individuals Predicts Viral Load Outcome

Publisher: The American Association of Immunologists

Date: 2011

DOI: 10.4049/JIMMUNOL.0903227

Abstract: The CTL response in HLA-B*27+ HIV-infected in iduals is characterized by an immunodominant response to a conserved epitope in gag p24 (aa 263–272, KRWIILGLNK KK10). Mutations resulting in substitution of the arginine (R264) at position 2 of this epitope have been identified as escape mutations. Nineteen HLA-B*27+ long-term nonprogressors were identified from an Australian cohort with an average follow-up of 16 y following infection. Viral and host genetic factors impacting on disease progression were determined at multiple time points. Twelve of 19 had wild-type sequences at codon 264 at all time points 7 of 19 carried CTL escape variants. Median viral load and CD4+ T cell counts were not significantly different between these groups at enrollment. Viral load, as judged by levels at their last visit (1,700 and 21,000 RNA copies/ml, respectively p = 0.01) or by time-weighted area under the curve was higher in the escape group (p = 0.02). Escape mutants at other HLA-B*27–restricted epitopes were uncommon. Moreover, host polymorphisms, such as CCR5Δ32, CCR2-64I, and SDF1-3′A, or breadth of TCR repertoire responding to KK10 did not segregate to wild-type or escape groups. Host and viral factors were examined for a relationship to viral load. The only factor to affect viral load was the presence of the R264 escape mutations at the immunodominant epitope. CTL escape at R264 in the KK10 epitope is a major determinant of subsequent viral load in these HLA-B*27+ in iduals.

Estimating initial viral levels during HIV/SIV reactivation from latency.

Publisher: American Society for Microbiology

Date: 15-01-2017

DOI: 10.1128/JVI.01667-17

Abstract: Human immunodeficiency virus (HIV) viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation posttreatment. This viral rebound arises from reactivation of in idual latently infected cells, which spread during ongoing rounds of productive infection. The level of virus produced by the initial in idual reactivating cells is not known, although it may have major implications for the ability of different immune interventions to control viral rebound. Here we use data from both HIV and simian immunodeficiency virus (SIV) treatment interruption studies to estimate the initial viral load postinterruption and thereby the initial in idual reactivation event. Using a barcoded virus (SIVmac239M) to track reactivation from in idual latent cells, we use the observed viral growth rates and frequency of reactivation to model the dynamics of reactivation to estimate that a single reactivated latent cell can produce an average viral load equivalent to ∼0.1 to 0.5 viral RNA (vRNA) copies/ml. Modeling of treatment interruption in HIV suggests an initial viral load equivalent of ∼0.6 to 1 vRNA copies/ml. These low viral loads immediately following latent cell reactivation provide a window of opportunity for viral control by host immunity, before further replication allows viral spread. This work shows the initial levels of viral production that must be controlled in order to successfully suppress HIV reactivation following treatment interruption. IMPORTANCE Current treatment for HIV is able to suppress viral replication and prevent disease progression. However, treatment cannot eradicate infection, because the virus lies silent within latently infected cells. If treatment is stopped, the virus usually rebounds above the level of detection within a few weeks. There are a number of approaches being tested aimed at either eradicating latently infected cells or controlling the virus if it returns. Studying both the small pool of latently infected cells and the early events during viral reactivation is difficult, because these involve very small levels of virus that are difficult to measure directly. Here, we combine experimental data and mathematical modeling to understand the very early events during viral reactivation from latency in both HIV infection of humans and SIV infection of monkeys. We find that the initial levels of virus are low, which may help in designing therapies to control early viral reactivation.

Within-host modeling of blood-stage malaria

Publisher: Wiley

Date: 11-08-2018

DOI: 10.1111/IMR.12697

Abstract: Malaria infection continues to be a major health problem worldwide and drug resistance in the major human parasite species, Plasmodium falciparum, is increasing in South East Asia. Control measures including novel drugs and vaccines are in development, and contributions to the rational design and optimal usage of these interventions are urgently needed. Infection involves the complex interaction of parasite dynamics, host immunity, and drug effects. The long life cycle (48 hours in the common human species) and synchronized replication cycle of the parasite population present significant challenges to modeling the dynamics of Plasmodium infection. Coupled with these, variation in immune recognition and drug action at different life cycle stages leads to further complexity. We review the development and progress of "within-host" models of Plasmodium infection, and how these have been applied to understanding and interpreting human infection and animal models of infection.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis

Publisher: Public Library of Science (PLoS)

Date: 16-10-2020

DOI: 10.1371/JOURNAL.PMED.1003394

Person-Specific Biomolecular Coronas Modulate Nanoparticle Interactions with Immune Cells in Human Blood

Publisher: American Chemical Society (ACS)

Date: 28-10-2020

DOI: 10.1021/ACSNANO.0C06679

Tear antibodies to SARS-CoV-2: implications for transmission

Publisher: Cold Spring Harbor Laboratory

Date: 04-08-2021

DOI: 10.1101/2021.08.02.21261479

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 SARS-CoV-2 specific IgG and IgA responses in human tears after either COVID-19 infection or vaccination. We recruited 16 subjects with COVID-19 infection an average of 7 months previously and 15 subjects before and 2 weeks after Comirnaty (Pfizer-BioNtech) vaccination. Plasma, saliva and basal tears were collected. Pre-pandemic plasma, saliva and basal tears from 11 in iduals were included as healthy controls. Antibody responses to 5 SARS-CoV-2 antigens were measured via multiplex. IgG antibodies to Spike and Nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS-CoV-2 infection in comparison to uninfected controls. While RBD-specific antibodies were detected in plasma, minimal RBD-specific antibodies were detected in tears and saliva. In 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. 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 neutralising antibodies may be low in the tears late following infection.

Developing a Tool for Auditing the Quality of Antibiotic Dispensing in Community Pharmacies: A Pilot Study

Publisher: MDPI AG

Date: 27-09-2022

DOI: 10.20944/PREPRINTS202209.0406.V1

Abstract: Background. The European Centre for Disease Prevention and Control describes the community pharmacist as gatekeeper to the quality of antibiotic use. The pharmacist has the responsibility to guard safe and effective antibiotic use however, little is known about how this is implemented in practice. Aims. To assess the feasibility of a method to audit the quality of antibiotic dispensing in community pharmacy practice and to explore antibiotic dispensing practices in Greece, Lithuania, Poland, and Spain. Methods. The Audit Project Odense methodology to audit antibiotic dispensing practice was adapted for use in community pharmacy practice. Community pharmacists registered antibiotic dispensing on a specifically developed registration chart and were asked to provide feedback on the registration method. Results. Altogether twenty pharmacists were recruited in four countries. They registered a total of 409 dispenses of oral antibiotics. Generally, pharmacists were positive about the feasibility of implementing the registration chart in practice. The frequency of checking for allergies, contraindications and interactions differed largely between the four countries. Pharmacists provided little advice to patients. The pharmacists rarely contacted prescribers. Conclusion. This tool seems to make it possible to get a useful picture of antibiotic dispensing patterns in community pharmacies. Dispensing practice does not seem to correspond with EU guidelines according to these preliminary results.

Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

Publisher: Public Library of Science (PLoS)

Date: 18-11-2010

DOI: 10.1371/JOURNAL.PPAT.1001198

Rapid Proliferation and Differentiation Impairs the Development of Memory CD8+ T Cells in Early Life

Publisher: The American Association of Immunologists

Date: 07-2014

DOI: 10.4049/JIMMUNOL.1400553

Abstract: Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. In this article, we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. Whereas adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life.

CD4 Depletion in SIV-Infected Macaques Results in Macrophage and Microglia Infection with Rapid Turnover of Infected Cells

Publisher: Public Library of Science (PLoS)

Date: 30-10-2014

DOI: 10.1371/JOURNAL.PPAT.1004467

HLA Class I Binding Motifs Derived from Random Peptide Libraries Differ at the COOH Terminus from Those of Eluted Peptides

Publisher: Rockefeller University Press

Date: 20-01-1997

DOI: 10.1084/JEM.185.2.367

Abstract: Recombinant HLA-A2, HLA-B8, or HLA-B53 heavy chain produced in Escherichia coli was combined with recombinant β2-microglobulin (β2m) and a pool of randomly synthesised nonamer peptides. This mixture was allowed to refold to form stable major histocompatability complex (MHC) class I complexes, which were then purified by gel filtration chromatography. The peptides bound to the MHC class I molecules were subsequently eluted and sequenced as a pool. Peptide binding motifs for these three MHC class I molecules were derived and compared with previously described motifs derived from analysis of naturally processed peptides eluted from the surface of cells. This comparison indicated that the peptides bound by the recombinant MHC class I molecules showed a similar motif to naturally processed and presented peptides, with the exception of the peptide COOH terminus. Whereas the motifs derived from naturally processed peptides eluted from HLA-A2 and HLA-B8 indicated a strong preference for hydrophobic amino acids at the COOH terminus, this preference was not observed in our studies. We propose that this difference reflects the effects of processing or transport on the peptide repertoire available for binding to MHC class I molecules in vivo.

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

DOI: 10.4049/JIMMUNOL.1400793

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

DOI: 10.1172/JCI.INSIGHT.172470

Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 (DQ 3.2)

Publisher: Oxford University Press (OUP)

Date: 06-1997

DOI: 10.1093/INTIMM/9.6.905

Abstract: HLA-DQ8 (A1*0301, B1*0302) and -DQ2 (A1*0501, B1*0201) are both associated with diseases such as insulin-dependent diabetes mellitus and coeliac disease. We used the technique of pool sequencing to look at the requirements of peptides binding to HLA-DQ8, and combined these data with naturally sequenced ligands and in vitro binding assays to describe a novel motif for HLA-DQ8. The motif, which has the same basic format as many HLA-DR molecules, consists of four or five anchor regions, in the positions from the N-terminus of the binding core of n, n + 3, n + 5/6 and n + 8, i.e. P1, P4, P6/7 and P9. P1 and P9 require negative or polar residues, with mainly aliphatic residues at P4 and P6/7. The features of the HLA-DQ8 motif were then compared to a pool sequence of peptides eluted from HLA-DQ2. A consensus motif for the binding of a common peptide which may be involved in disease pathogenesis is described. Neither of the disease-associated alleles HLA-DQ2 and -DQ8 have Asp at position 57 of the beta-chain. This Asp, if present, may form a salt bridge with an Arg at position 79 of the alpha-chain and so alter the binding specificity of P9. HLA-DQ2 and -DQ8 both appear to prefer negatively charged amino acids at P9. In contrast, HLA-DQ7 (A1*0301, B1*0301), which is not associated with diabetes, has Asp at beta 57, allowing positively charged amino acids at P9. This analysis of the sequence features of DQ-binding peptides suggests molecular characteristics which may be useful to predict epitopes involved in disease pathogenesis.

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.

Homogenization of TCR Repertoires within Secondary CD62Lhigh and CD62Llow Virus-Specific CD8+ T Cell Populations

Publisher: The American Association of Immunologists

Date: 15-06-2008

DOI: 10.4049/JIMMUNOL.180.12.7938

Abstract: Influenza virus-specific CD8+ T cell clonotypes generated and maintained in C57BL/6J mice after respiratory challenge were found previously to distribute unequally between the CD62Llow “effector” (TEM) and CD62Lhigh “central” (TCM) memory subsets. Defined by the CDR3β sequence, most of the prominent TCRs were represented in both the CD62Lhigh and CD62Llow subsets, but there was also a substantial number of erse, but generally small, CD62Lhigh-only clonotypes. The question asked here is how secondary challenge influences both the ersity and the continuity of TCR representation in the TCM and TEM subsets generated following primary exposure. The experiments use single-cell RT-PCR to correlate clonotypic composition with CD62L phenotype for secondary influenza-specific CD8+ T cell responses directed at the prominent DbNP366 and DbPA224 epitopes. In both the acute and long-term memory phases of the recall responses to these epitopes, we found evidence of a convergence of TCR repertoire expression for the CD62Llow and CD62Lhigh populations. In fact, unlike the primary response, there were no significant differences in clonotypic ersity between the CD62Llow and CD62Lhigh subsets. This “TCR homogenization” for the CD62Lhigh and CD62Llow CD8+ populations recalled after secondary challenge indicates common origin, most likely from the high prevalence populations in the CD62Lhigh central memory set. Our study thus provides key insights into the TCR ersity spectrum for CD62Lhigh and CD62Llow T cells generated from a normal, unmanipulated T cell repertoire following secondary challenge. A better understanding of TCR selection and maintenance has implications for improved vaccine and immunotherapy protocols.

Mining the mechanisms of an HIV vaccine

Publisher: Springer Science and Business Media LLC

Date: 07-2012

DOI: 10.1038/NM.2858

Cell-autonomous and environmental contributions to the interstitial migration of T cells

Publisher: Springer Science and Business Media LLC

Date: 10-07-2010

DOI: 10.1007/S00281-010-0212-1

A stochastic model of cytotoxic T cell responses

Publisher: Elsevier BV

Date: 05-2004

DOI: 10.1016/J.JTBI.2003.12.011

Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination

Publisher: Proceedings of the National Academy of Sciences

Date: 05-12-2006

DOI: 10.1073/PNAS.0608907103

Abstract: Public responses where identical T cell receptors (TCRs) are clonally dominant and shared between different in iduals are a common characteristic of CD8 + T cell-mediated immunity. Focusing on TCR sharing, we analyzed ≈3,400 TCR β chains (TCRβs) from mouse CD8 + T cells responding to the influenza A virus D b NP 366 and D b PA 224 epitopes. Both the “public” D b NP 366 -specific and “private” D b PA 224 -specific TCR repertoires contain a high proportion (≈36%) of shared TCRβs, although the numbers of mice sharing TCRβs in each repertoire varies greatly. Sharing of both the TCRβ amino acid and TCRβ nucleotide sequence was negatively correlated with the prevalence of random nucleotide additions in the sequence. However, the extent of TCRβ amino acid sequence sharing among mice was strongly correlated with the level of ersity in the encoding nucleotide sequences, suggesting that a key feature of public TCRs is that they can be made in a variety of ways. Using a computer simulation of random V(D)J recombination, we estimated the relative production frequencies and variety of production mechanisms for TCRβ sequences and found strong correlations with the sharing of both TCRβ amino acid sequences and TCRβ nucleotide sequences. The overall conclusion is that “convergent recombination,” rather than a bias in recombination or subsequent selection, provides the mechanistic basis for TCR sharing between in iduals responding to identical peptide plus MHC class I glycoprotein complexes.

Preferential invasion of reticulocytes during late-stage Plasmodium berghei infection accounts for reduced circulating reticulocyte levels

Publisher: Elsevier BV

Date: 11-2006

DOI: 10.1016/J.IJPARA.2006.07.009

Abstract: Insufficient circulating reticulocytes have been observed during severe malarial anaemia in both human and murine infection, and are often attributed to reduced production of red cell precursors. However, a number of Plasmodium species display a preference for invading reticulocytes rather than erythrocytes. Thus, the reduction in circulating reticulocyte numbers may arise as a result both of increased parasitization and lysis of reticulocytes, as well as decreased production. We have analysed both circulating reticulocyte numbers and the percentage of infected reticulocytes during murine Plasmodium berghei infection. We found a large reduction in circulating numbers when compared with an equivalent chemically induced anaemia. However, mathematical analysis of parasite and red cell numbers revealed the preference of P. berghei for reticulocytes to be approximately 150-fold over that for erythrocytes, leading to increased destruction of reticulocytes. Although erythropoietic suppression is evident during the first week of P. berghei infection, this preferential infection and destruction of reticulocytes is sufficient to mediate ongoing reduced levels of circulating reticulocytes during the latter stages of infection, following compensatory erythropoiesis in response to haemolytic anaemia.

Kinetics of Virus-Specific CD8 ⁺ T Cells and the Control of Human Immunodeficiency Virus Infection

Publisher: American Society for Microbiology

Date: 15-09-2004

DOI: 10.1128/JVI.78.18.10096-10103.2004

Abstract: Several primate models indicate that cytotoxic T lymphocyte-inducing vaccines may be unable to prevent human immunodeficiency virus infection but may have a long-term benefit in controlling viral replication and delaying disease progression. Here we show that analysis of the kinetics of antigen-specific CD8 + T-cell expansion suggests a delay in activation following infection that allows unimpeded early viral replication. Viral kinetics do not differ between controls and vaccinees during this delay phase. An increase in virus-specific CD8 + T-cell numbers around day 10 postinfection coincides with a slowing in viral replication in vaccinees and reduces peak viral loads by around 1 log. However, this response is too little too late to prevent establishment of persistent infection.

Benefits of memory

Publisher: Springer Science and Business Media LLC

Date: 12-2000

DOI: 10.1038/82689

Replacement of Red and Processed Meat With Other Food Sources of Protein and the Risk of Type 2 Diabetes in European Populations: The EPIC-InterAct Study

Publisher: American Diabetes Association

Date: 31-08-2020

DOI: 10.2337/DC20-1038

Abstract: There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact. The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 in iduals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis. There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat (50 g/day) with cheese (HR 0.90, 95% CI 0.83–0.97) (30 g/day), yogurt (0.90, 0.86–0.95) (70 g/day), nuts (0.90, 0.84–0.96) (10 g/day), or cereals (0.92, 0.88–0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes. Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.

High-Potency Human Immunodeficiency Virus Vaccination Leads to Delayed and Reduced CD8 ⁺ T-Cell Expansion but Improved Virus Control

Publisher: American Society for Microbiology

Date: 08-2005

DOI: 10.1128/JVI.79.15.10059-10062.2005

Abstract: CD8 + T lymphocytes are thought to play an important role in the control of acute and chronic human immunodeficiency virus infections. However, there is a significant delay between infection and the first observed increase in virus-specific CD8 + T-cell numbers. Prior to this time, viral kinetics are not significantly different between controls and vaccinees. Surprisingly, higher initial virus-specific CD8 + T-cell numbers lead to a longer delay prior to initial CD8 + T-cell expansion, and slower CD8 + T-cell increases. Nevertheless, higher initial CD8 + T-cell numbers were associated with reduced peak and chronic viral loads and reduced CD4 + T-cell depletion.

Terminal deoxynucleotidyltransferase is required for the establishment of private virus-specific CD8+ TCR repertoires and facilitates optimal CTL responses.

Publisher: The American Association of Immunologists

Date: 15-08-2008

DOI: 10.4049/JIMMUNOL.181.4.2556

Abstract: Virus-immune CD8+ TCR repertoires specific for particular peptide-MHC class I complexes may be substantially shared between (public), or unique to, in iduals (private). Because public TCRs can show reduced TdT-mediated N-region additions, we analyzed how TdT shapes the heavily public (to DbNP366) and essentially private (to DbPA224) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2b) mice. The DbNP366-specific CTL response was virtually clonal in TdT−/− B6 animals, with one of the three public clonotypes prominent in the wild-type (wt) response consistently dominating the TdT−/− set. Furthermore, this massive narrowing of TCR selection for DbNP366 reduced the magnitude of DbNP366-specific CTL response in the virus-infected lung. Conversely, the DbPA224-specific responses remained comparable in both magnitude and TCR ersity within in idual TdT−/− and wt mice. However, the extent of TCR ersity across the total population was significantly reduced, with the consequence that the normally private wt DbPA224-specific repertoire was now substantially public across the TdT−/− mouse population. The key finding is thus that the role of TdT in ensuring enhanced ersity and the selection of private TCR repertoires promotes optimal CD8+ T cell immunity, both within in iduals and across the species as a whole.

Public attitudes towards research participation during an infectious disease pandemic: a qualitative study across four European countries

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/S0140-6736(16)32287-5

Where Have All the Parasites Gone? Modelling Early Malaria Parasite Sequestration Dynamics

Publisher: Public Library of Science (PLoS)

Date: 18-02-2013

DOI: 10.1371/JOURNAL.PONE.0055961

Density-Dependent Blood Stage Plasmodium falciparum Suppresses Malaria Super-Infection in a Malaria Holoendemic Population

Publisher: American Society of Tropical Medicine and Hygiene

Date: 06-11-2013

DOI: 10.4269/AJTMH.13-0049

SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection

Publisher: Cold Spring Harbor Laboratory

Date: 09-12-2021

DOI: 10.1101/2021.12.08.21267417

Abstract: The emergence of SARS-CoV-2 Omicron, first identified in Botswana and South Africa, may compromise vaccine effectiveness and the ability of antibodies triggered by previous infection to protect against re-infection (1). Here we investigated whether Omicron escapes antibody neutralization in South Africans, either previously SARS-CoV-2 infected or uninfected, who were vaccinated with Pfizer BNT162b2. We also investigated if Omicron requires the ACE2 receptor to infect cells. We isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralization of this virus relative to an ancestral SARS-CoV-2 strain with the D614G mutation, observing that Omicron still required ACE2 to infect. For neutralization, blood s les were taken soon after vaccination, so that vaccine elicited neutralization was close to peak. Neutralization capacity of the D614G virus was much higher in infected and vaccinated versus vaccinated only participants but both groups had 22-fold Omicron escape from vaccine elicited neutralization. Previously infected and vaccinated in iduals had residual neutralization predicted to confer 73% protection from symptomatic Omicron infection, while those without previous infection were predicted to retain only about 35%. Both groups were predicted to have substantial protection from severe disease. These data support the notion that high neutralization capacity elicited by a combination of infection and vaccination, and possibly boosting, could maintain reasonable effectiveness against Omicron. A waning neutralization response is likely to decrease vaccine effectiveness below these estimates. However, since protection from severe disease requires lower neutralization levels and involves T cell immunity, such protection may be maintained.

Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Publisher: Proceedings of the National Academy of Sciences

Date: 25-10-2010

DOI: 10.1073/PNAS.1010586107

Abstract: Adaptive T-cell immunity relies on the recruitment of antigen-specific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. Despite the enormous clonotypic ersity that resides within the naïve T-cell pool, interin idual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide–major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or “public,” TCRs in specific memory T-cell populations. According to this model, TCR sharing between in iduals is directly related to TCR production frequency this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8 + TCRβ repertoire in mice. Within defined segments of the naïve CD8 + T-cell repertoire, TCRβ sequences with convergent features were ( i ) present at higher copy numbers within in idual mice and ( ii ) shared between in idual mice. Thus, the naïve CD8 + T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for in idual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8 + T-cell clonotypes, which can exert profound biological effects during acute infectious processes.

The origin of genetic diversity in HIV-1

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1016/J.VIRUSRES.2012.06.015

Abstract: One of the hallmarks of HIV infection is the rapid development of a genetically complex population (quasispecies) from an initially limited number of infectious particles. Genetic ersity remains one of the major obstacles to eradication of HIV. The viral quasispecies can respond rapidly to selective pressures, such as that imposed by the immune system and antiretroviral therapy, and frustrates vaccine design efforts. Two unique features of retroviral replication are responsible for the unprecedented variation generated during infection. First, mutations are frequently introduced into the viral genome by the error prone viral reverse transcriptase and through the actions of host cellular factors, such as the APOBEC family of nucleic acid editing enzymes. Second, the HIV reverse transcriptase can utilize both copies of the co-packaged viral genome in a process termed retroviral recombination. When the co-packaged viral genomes are genetically different, retroviral recombination can lead to the shuffling of mutations between viral genomes in the quasispecies. This review outlines the stages of the retroviral life cycle where genetic variation is introduced, focusing on the principal mechanisms of mutation and recombination. Understanding the mechanistic origin of genetic ersity is essential to combating HIV.

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.

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.

Central memory CD4+ T cells are preferential targets of double infection by HIV-1

Publisher: Springer Science and Business Media LLC

Date: 11-11-2015

DOI: 10.1186/S12985-015-0415-0

APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome

Publisher: Springer Science and Business Media LLC

Date: 12-2012

DOI: 10.1186/1742-4690-9-113

Abstract: The human immune proteins APOBEC3G and APOBEC3F (hA3G and hA3F) induce destructive G-to-A changes in the HIV genome, referred to as ‘hypermutation’. These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virions. Therefore they are expected to also co-mutate the HIV genome. Here we investigate the mutational footprints of hA3G and hA3F in a large population of full genome HIV-1 sequences from naturally infected patients to uniquely identify sequences hypermutated by either or both of these proteins. We develop a method of identification based on the representation of hA3G and hA3F target and product motifs that does not require an alignment to a parental/consensus sequence. Out of nearly 100 hypermutated HIV-1 sequences only one sequence from the HIV-1 outlier group showed clear signatures of co-mutation by both proteins. The remaining sequences were affected by either hA3G or hA3F. Using a novel method of identification of HIV sequences hypermutated by the hA3G and hA3F enzymes, we report a very low rate of co-mutation of full-length HIV sequences, and discuss the potential mechanisms underlying this.

The effect of early versus delayed challenge after vaccination in controlling SHIV 89.6P infection

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1016/J.VIROL.2008.07.042

Reverse immunogenetics: from HLA-disease associations to vaccine candidates

Publisher: Elsevier BV

Date: 1996

DOI: 10.1016/1357-4310(96)88757-0

Abstract: Analysis of the human leukocyte antigens (HLA) in patients with either infectious or autoimmune diseases has led to the identification of several HLA alleles associated with either resistance or susceptibility to disease. Understanding the role of HLA molecules in the presentation of peptide antigens to T cells has led to the use of 'reverse immunogenetics': a novel approach to analysing the key antigenic peptides that are presented by the relevant HLA molecules. Recent advances in the analysis of naturally occurring peptides bound to HLA molecules has allowed the direct identification of antigenic peptides from living cells and has supported the development of vaccine candidates, such as the liver-stage antigen 1 in malaria.

Towards actionable international comparisons of health system performance: expert revision of the OECD framework and quality indicators

Publisher: Oxford University Press (OUP)

Date: 10-03-2015

DOI: 10.1093/INTQHC/MZV004

Abstract: To review and update the conceptual framework, indicator content and research priorities of the Organisation for Economic Cooperation and Development's (OECD) Health Care Quality Indicators (HCQI) project, after a decade of collaborative work. A structured assessment was carried out using a modified Delphi approach, followed by a consensus meeting, to assess the suite of HCQI for international comparisons, agree on revisions to the original framework and set priorities for research and development. International group of countries participating to OECD projects. Members of the OECD HCQI expert group. A reference matrix, based on a revised performance framework, was used to map and assess all seventy HCQI routinely calculated by the OECD expert group. A total of 21 indicators were agreed to be excluded, due to the following concerns: (i) relevance, (ii) international comparability, particularly where heterogeneous coding practices might induce bias, (iii) feasibility, when the number of countries able to report was limited and the added value did not justify sustained effort and (iv) actionability, for indicators that were unlikely to improve on the basis of targeted policy interventions. The revised OECD framework for HCQI represents a new milestone of a long-standing international collaboration among a group of countries committed to building common ground for performance measurement. The expert group believes that the continuation of this work is paramount to provide decision makers with a validated toolbox to directly act on quality improvement strategies.

A kinetic model of bone marrow neutrophil production that characterizes late phenotypic maturation

Publisher: American Physiological Society

Date: 04-2007

DOI: 10.1152/AJPREGU.00627.2006

Abstract: Acute inflammatory stimuli rapidly mobilize neutrophils from the bone marrow by shortening postmitotic maturation time and releasing younger neutrophils however, the kinetics of this change in maturation time remains unknown. We propose a kinetic model that examines the rate of change in neutrophil average age at exit from the bone marrow during active mobilization to quantify this response and use this model to examine the temporal profile of late neutrophil phenotypic maturation. Total and CD10 − /CD16 low circulating neutrophils were quantified in cardiac surgery patients during extracorporeal circulation (ECC). Net growth in the circulating neutrophil pool occurred during the procedural (0.04 ± 0.02 × 10 9 ·l −1 ·min −1 ), warming (0.14 ± 0.02 × 10 9 ·l −1 ·min −1 ), and weaning (0.12 ± 0.06 × 10 9 ·l −1 ·min −1 ) phases of ECC. When applied to our differential equation mathematical model, these results predict that neutrophil average age at exit from the bone marrow decreased continually during ECC, resulting in average neutrophil release 8.44 ± 2.20 h earlier during the weaning phase than at the beginning of ECC s ling. Modeling of concurrent changes in CD10 − /CD16 low neutrophil numbers indicates that CD10 expression is directly related to neutrophil mean age and predicts that the proportion of mobilizable postmitotic neutrophils that are CD10 + increases from 64 to 81% during these s led 8.4 h of maturation.

Persistent Survival of Prevalent Clonotypes within an Immunodominant HIV Gag-Specific CD8+ T Cell Response

Publisher: The American Association of Immunologists

Date: 2011

DOI: 10.4049/JIMMUNOL.1001807

Abstract: CD8+ T cells play a significant role in the control of HIV replication, yet the associated qualitative and quantitative factors that determine the outcome of infection remain obscure. In this study, we examined Ag-specific CD8+ TCR repertoires longitudinally in a cohort of HLA-B*2705+ long-term nonprogressors with chronic HIV-1 infection using a combination of molecular clonotype analysis and polychromatic flow cytometry. In each case, CD8+ T cell populations specific for the immunodominant p24 Gag epitope KRWIILGLNK (KK10 residues 263–272) and naturally occurring variants thereof, restricted by HLA-B*2705, were studied at multiple time points in addition, comparative data were collected for CD8+ T cell populations specific for the CMV pp65 epitope NLVPMVATV (NV9 residues 495–503), restricted by HLA-A*0201. Dominant KK10-specific clonotypes persisted for several years and exhibited greater stability than their contemporaneous NV9-specific counterparts. Furthermore, these dominant KK10-specific clonotypes exhibited cross-reactivity with antigenic variants and expressed significantly higher levels of CD127 (IL-7Rα) and Bcl-2. Of note, we also found evidence that promiscuous TCR α-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR β-chain prevalence. Taken together, these data suggest that an antiapoptotic phenotype and the ability to cross-recognize variant epitopes contribute to clonotype longevity and selection within the peripheral memory T cell pool in the presence of persistent infection with a genetically unstable virus.

Effects of Antibody on Viral Kinetics in Simian/Human Immunodeficiency Virus Infection: Implications for Vaccination

Publisher: American Society for Microbiology

Date: 15-05-2004

DOI: 10.1128/JVI.78.10.5520-5522.2004

Abstract: Passive antibody treatment of macaques prior to simian/human immunodeficiency virus infection produces “sterilizing immunity” in some animals and long-term reductions in viral loads in others. Analysis of viral kinetics suggests that antibody mediates sterilizing immunity by its effects on the initial viral inoculum. By contrast, reduction in peak viral load later in infection prevents CD4 depletion and contributes to long-term viral control.

Antagonists or altruists: do viral mutants modulate T-cell responses?

Publisher: Elsevier BV

Date: 09-1995

DOI: 10.1016/0167-5699(95)80020-4

Abstract: The ability of altered peptide ligands (APLs) to modify or downregulate T-cell responses in vitro has generated much interest. Recently, it was proposed that viral variants may contain mutations in cytotoxic T lymphocyte (CTL) epitopes that allow mutual antagonism, and that these combine to downregulate the host immune response. Here, Miles Davenport discusses some inherent problems with this simple model and proposes a closer evaluation of the effects of viral competition on host-viral interactions.

The T cell repertoire in infection and vaccination: implications for control of persistent viruses

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1016/J.COI.2007.04.001

Abstract: Most currently available vaccines target acute infectious agents such as polio, smallpox and influenza virus. The development of vaccines to persistent infectious agents has proven much more difficult. Although it is possible to generate T cell responses to such viruses, these responses are currently unable to prevent the establishment of infection, and immune control may be lost during the chronic phase. Recent advances have increased our understanding of the interactions between persistent viruses and the available T cell repertoire, and will guide approaches to the generation and maintenance of an 'ideal' T cell response.

Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection

Publisher: Springer Science and Business Media LLC

Date: 29-04-2021

DOI: 10.1038/S41577-021-00550-X

A role for super-spreaders in carrying malaria parasites across the months-long dry season

Publisher: Cold Spring Harbor Laboratory

Date: 02-05-2022

DOI: 10.1101/2022.04.28.22274398

Abstract: In malaria endemic regions, transmission of Plasmodium falciparum parasites is often seasonal with very low transmission during the dry season and high transmission in the wet season. Parasites survive the dry season within some in iduals who experience prolonged carriage of parasites and are thought to ‘seed’ infection in the next transmission season. We use a combination of mathematical simulations and data analysis to characterise dry season carriers and their role in the subsequent transmission season. Simulating the life-history of in iduals experiencing repeated exposure to infection predicts that dry season carriage is more likely in the oldest, most exposed and most immune in iduals. This hypothesis is supported by data from a longitudinal study in Mali that shows that carriers are significantly older, experience a higher biting rate at the beginning of the transmission season and develop clinical malaria later than non-carriers. Further, since the most exposed in iduals in a community are most likely to be dry season carriers, we show that this is predicted to enable a more than 2-fold faster spread of parasites into the mosquito population at the start of the subsequent wet season.

Analysis of the In Vivo Turnover of CD4+ T-Cell Subsets in Chronically SIV-Infected Sooty Mangabeys

Publisher: Public Library of Science (PLoS)

Date: 26-05-2016

DOI: 10.1371/JOURNAL.PONE.0156352

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

DOI: 10.1371/JOURNAL.PPAT.1005000

Effect of outpatient antibiotics for urinary tract infections on antimicrobial resistance among commensal Enterobacteriaceae: a multinational prospective cohort study

Publisher: Elsevier BV

Date: 09-2018

DOI: 10.1016/J.CMI.2017.12.026

Abstract: We quantified the impact of antibiotics prescribed in primary care for urinary tract infections (UTIs) on intestinal colonization by ciprofloxacin-resistant (CIP-RE) and extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), while accounting for household clustering. Prospective cohort study from January 2011 to August 2013 at primary care sites in Belgium, Poland and Switzerland. We recruited outpatients requiring antibiotics for suspected UTIs or asymptomatic bacteriuria (exposed patients), outpatients not requiring antibiotics (non-exposed patients), and one to three household contacts for each patient. Faecal s les were tested for CIP-RE, ESBL-PE, nitrofurantoin-resistant Enterobacteriaceae (NIT-RE) and any Enterobacteriaceae at baseline (S1), end of antibiotics (S2) and 28 days after S2 (S3). We included 300 households (205 exposed, 95 non-exposed) with 716 participants. Most exposed patients received nitrofurans (86 42%) or fluoroquinolones (76 37%). CIP-RE were identified in 16% (328/2033) of s les from 202 (28%) participants. Fluoroquinolone treatment caused transient suppression of Enterobacteriaceae (S2) and subsequent two-fold increase in CIP-RE prevalence at S3 (adjusted prevalence ratio (aPR) 2.0, 95% CI 1.2-3.4), with corresponding number-needed-to-harm of 12. Nitrofurans had no impact on CIP-RE (aPR 1.0, 95% CI 0.5-1.8) or NIT-RE. ESBL-PE were identified in 5% (107/2058) of s les from 71 (10%) participants, with colonization not associated with antibiotic exposure. Household exposure to CIP-RE or ESBL-PE was associated with increased in idual risk of colonization: aPR 1.8 (95% CI 1.3-2.5) and 3.4 (95% CI 1.3-9.0), respectively. These findings support avoidance of fluoroquinolones for first-line UTI therapy in primary care, and suggest potential for interventions that interrupt household circulation of resistant Enterobacteriaceae.

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.

The search for an HIV cure: tackling latent infection

Publisher: Elsevier BV

Date: 07-2013

DOI: 10.1016/S1473-3099(13)70043-4

In Silico Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance.

Publisher: American Society for Microbiology

Date: 12-2018

DOI: 10.1128/AAC.01292-18

Abstract: Antimalarial treatment currently relies on an artemisinin derivative and a longer-acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated.

Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Publisher: The Royal Society

Date: 30-06-2010

DOI: 10.1098/RSPB.2010.0972

Abstract: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

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.

Characterising the effect of antimalarial drugs on the maturation and clearance of murine blood-stage Plasmodium parasites in vivo

Publisher: Elsevier BV

Date: 12-2017

DOI: 10.1016/J.IJPARA.2017.05.009

Abstract: The artemisinins are the first-line therapy for severe and uncomplicated malaria, since they cause rapid declines in parasitemia after treatment. Despite this, in vivo mechanisms underlying this rapid decline remain poorly characterised. The overall decline in parasitemia is the net effect of drug inhibition of parasites and host clearance, which competes against any ongoing parasite proliferation. Separating these mechanisms in vivo was not possible through measurements of total parasitemia alone. Therefore, we employed an adoptive transfer approach in which C57BL/6J mice were transfused with Plasmodium berghei ANKA strain-infected, fluorescent red blood cells, and subsequently drug-treated. This approach allowed us to distinguish between the initial drug-treated generation of parasites (Gen

Impact ofPlasmodium falciparumCoinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children

Publisher: Oxford University Press (OUP)

Date: 03-11-2015

DOI: 10.1093/INFDIS/JIV525

Vaccination-Induced Noncytolytic Effects in the Acute Phase of SHIV Infection

Publisher: Public Library of Science (PLoS)

Date: 30-11-2010

DOI: 10.1371/JOURNAL.PONE.0015083

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.

HIV-1 Mutation and Recombination Rates Are Different in Macrophages and T-cells

Publisher: MDPI AG

Date: 22-04-2016

DOI: 10.3390/V8040118

A comparative study of electro-dewatering process performance for activated and digested wastewater sludge

Publisher: Elsevier BV

Date: 02-2018

DOI: 10.1016/J.WATRES.2017.10.063

Abstract: Electro-dewatering (EDW) is an alternative emerging and energy-efficient technology that provides improved liquid/solids separations in the dewatering of wastewater sludge. The EDW technology is not only an innovative dewatering method for significantly reducing the volume of wastewater sludge before re-utilization or disposal, but is also a promising emerging method which may potentially be used for decontamination purposes. In this study, the influence of the sludge properties (e.g. electrical conductivity, zeta potential, specific cake resistance, among others) on their mechanical and electrical behaviour in terms of dewaterability and electro-dewaterability, the applied current (current density from 20 to 80 A/m

Relating In Vitro Neutralization Level and Protection in the CVnCoV (CUREVAC) Trial

Publisher: Oxford University Press (OUP)

Date: 02-2022

DOI: 10.1093/CID/CIAC075

Abstract: The vaccine candidate CVnCoV (CUREVAC) showed surprisingly low efficacy in a recent phase 3 trial compared with other messenger RNA (mRNA) vaccines. Here we show that the low efficacy follows from the dose used and the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and is predicted by the neutralizing antibody response induced by the vaccine.

Method for assessing the similarity between subsets of the T cell receptor repertoire

Publisher: Elsevier BV

Date: 2008

DOI: 10.1016/J.JIM.2007.09.016

Abstract: The CD8+ T cell response is important in the control of many viral and other infections. There have been many studies aimed at better understanding the influence of T cell receptor ersity on immune responses and the evolution of the T cell receptor repertoire over time and through the various stages of immune responses to infection. In recent years, there has been an increase in both the number of studies using T cell receptor data and the volume of T cell receptor data generated per study. Appropriate analytical tools are required to analyse this data. We present a robust approach to assessing the similarity between s les of the T cell receptor repertoire, which we demonstrate on published data of subsets of the influenza A virus D(b)NP366(-) and D(b)PA224(-)specific CD8+ T cell responses in mice sorted on the expression of CD62L, which is a marker distinguishing central and effector memory cells.

Extraction and characterization of the rhesus macaque T‐cell receptor β‐chain genes

Publisher: Wiley

Date: 09-06-2009

DOI: 10.1038/ICB.2009.38

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.

Understanding the mechanisms and limitations of immune control of HIV

Publisher: Wiley

Date: 12-03-2007

DOI: 10.1111/J.1600-065X.2006.00485.X

Gammaherpesvirus latency induces antibody-associated thrombocytopenia in mice

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.JAUT.2012.11.005

Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models

Publisher: Springer Science and Business Media LLC

Date: 02-11-2020

DOI: 10.1038/S41577-020-00471-1

A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing

Publisher: The American Association of Immunologists

Date: 04-2011

DOI: 10.4049/JIMMUNOL.1003898

Abstract: The human naive T cell repertoire is the repository of a vast array of TCRs. However, the factors that shape their hierarchical distribution and relationship with the memory repertoire remain poorly understood. In this study, we used polychromatic flow cytometry to isolate highly pure memory and naive CD8+ T cells, stringently defined with multiple phenotypic markers, and used deep sequencing to characterize corresponding portions of their respective TCR repertoires from four in iduals. The extent of interin idual TCR sharing and the overlap between the memory and naive compartments within in iduals were determined by TCR clonotype frequencies, such that higher-frequency clonotypes were more commonly shared between compartments and in iduals. TCR clonotype frequencies were, in turn, predicted by the efficiency of their production during V(D)J recombination. Thus, convergent recombination shapes the TCR repertoire of the memory and naive T cell pools, as well as their interrelationship within and between in iduals.

Does Cytolysis by CD8+ T Cells Drive Immune Escape in HIV Infection?

Publisher: The American Association of Immunologists

Date: 11-2010

DOI: 10.4049/JIMMUNOL.1002204

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.

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.

Risk of Plasmodium vivax recurrences follows a 30-70 rule and indicates relapse heterogeneity in the population

Publisher: Cold Spring Harbor Laboratory

Date: 20-05-2022

DOI: 10.1101/2022.05.18.22275180

Abstract: A key characteristic of Plasmodium vivax parasites is their ability to adopt a latent liver-stage form called hypnozoites, able to cause relapse of infection months or years after a primary infection. Relapses of infection through hypnozoite activation are a major contributor to blood-stage infections in P vivax endemic regions and are thought to be influenced by factors such as febrile infections, immunity, and transmission intensity. Some of these factors may cause temporary changes in hypnozoite activation over time, leading to ‘temporal heterogeneity’ in reactivation risk. In addition, variation in exposure to infection may be a longer-term characteristic of in iduals that leads to ‘population heterogeneity’ in hypnozoite activation. We analyze data on risk of P vivax in two previously published data sets from Papua New Guinea and the Thailand-Myanmar border region. Modeling different mechanisms of reactivation risk, we find strong evidence for population heterogeneity, with 30% of patients having almost 70% of all P vivax infections. Model fitting and data analysis indicates that in idual variation in relapse risk is a primary source of heterogeneity of P vivax risk of recurrences.

Innate Immunity Induced by Plasmodium Liver Infection Inhibits Malaria Reinfections

Publisher: American Society for Microbiology

Date: 03-2015

DOI: 10.1128/IAI.02796-14

Abstract: Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-γ). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.

Footprint of APOBEC3 on the Genome of Human Retroelements

Publisher: American Society for Microbiology

Date: 15-07-2013

DOI: 10.1128/JVI.00298-13

Abstract: Almost half of the human genome is composed of transposable elements. The genomic structures and life cycles of some of these elements suggest they are a result of waves of retroviral infection and transposition over millions of years. The reduction of retrotransposition activity in primates compared to that in nonprimates, such as mice, has been attributed to the positive selection of several antiretroviral factors, such as apolipoprotein B mRNA editing enzymes. Among these, APOBEC3G is known to mutate G to A within the context of G G in the genome of endogenous as well as several exogenous retroelements (the underlining marks the G that is mutated). On the other hand, APOBEC3F and to a lesser extent other APOBEC3 members induce G-to-A changes within the nucleotide G A. It is known that these enzymes can induce deleterious mutations in the genome of retroviral sequences, but the evolution and/or inactivation of retroelements as a result of mutation by these proteins is not clear. Here, we analyze the mutation signatures of these proteins on large populations of long interspersed nuclear element (LINE), short interspersed nuclear element (SINE), and endogenous retrovirus (ERV) families in the human genome to infer possible evolutionary pressure and/or hypermutation events. Sequence context dependency of mutation by APOBEC3 allows investigation of the changes in the genome of retroelements by inspecting the depletion of G and enrichment of A within the APOBEC3 target and product motifs, respectively. Analysis of approximately 22,000 LINE-1 (L1), 24,000 SINE Alu, and 3,000 ERV sequences showed a footprint of GG→AG mutation by APOBEC3G and GA→AA mutation by other members of the APOBEC3 family (e.g., APOBEC3F) on the genome of ERV-K and ERV-1 elements but not on those of ERV-L, LINE, or SINE.

The effects of thymic selection on the range of T cell cross‐reactivity

Publisher: Wiley

Date: 12-2005

DOI: 10.1002/EJI.200535098

Six unrelated HLA-DR-matched adults recognize identical CD4+ T cell epitopes from influenza A haemagglutinin that are not simply peptides with high HLA-DR binding affinities.

Publisher: Oxford University Press (OUP)

Date: 02-1998

DOI: 10.1093/INTIMM/10.2.211

Abstract: Influenza A/Beijing/32/92 (H3N2) haemagglutinin (HA)-specific short-term CD4+ T cell lines were generated from six unrelated HLA-DR0701, 1501 positive adults (aged 27-60 years) 3 months following administration of an influenza subunit vaccine containing HA A/Beijing/32/92. Epitope recognition was examined using 118 HA A/Beijing/32/92-specific 16mer peptides which overlapped by 11 residues and which spanned the entire molecule. Following influenza vaccination the donors recognized identical HA peptides. The selected peptides represented HA regions which have been free from extensive drift mutation since the emergence of human H3N2 influenza A strains. Using DAP DR7.0701 cells (a murine cell line expressing HLA-DR0701) as antigen-presenting cells the majority of CD4+ T cell responses were shown to be HLA-DR0701 restricted. The relationship between HA peptide recognition and relative strength of HA peptide-HLA-DR0701 binding was then explored in a competition assay with biotinylated CLIP peptide. Although peptides representing dominant HA epitopes bound to DR0701, the relationship between relative strength of binding and immunodominance was complex, and many strongly binding peptides, particularly those with glycosylation sites and showing inter-strain variation, were not recognized. These results illustrate the control HLA class II exerts over CD4+ T cell HA epitope selection in unrelated adult humans. Immunodominance appears not to be directly related to the relative strength of HA peptide-HLA class II binding, and thus reflects complex interactions between antigen processing, intracellular competition for HLA binding, TCR repertoires and repeated exposure to different strains of influenza A viruses.

Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization

Publisher: Springer Science and Business Media LLC

Date: 23-12-2021

DOI: 10.1038/S41586-021-04387-1

Abstract: The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections 1 . Here we investigated Omicron escape from neutralization by antibodies from South African in iduals vaccinated with Pfizer BNT162b2. We used blood s les taken soon after vaccination from in iduals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated in iduals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches.

Time-to-infection by Plasmodium falciparum is largely determined by random factors

Publisher: Springer Science and Business Media LLC

Date: 30-01-2015

DOI: 10.1186/S12916-014-0252-9

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Publisher: American Society for Clinical Investigation

Date: 06-07-2017

DOI: 10.1172/JCI.INSIGHT.92750

HIV-1 Variation Diminishes CD4 T Lymphocyte Recognition

Publisher: Rockefeller University Press

Date: 16-11-1998

DOI: 10.1084/JEM.188.10.1785

Abstract: Effective long-term antiviral immunity requires specific cytotoxic T lymphocytes and CD4+ T lymphocyte help. Failure of these helper responses can be a principle cause of viral persistence. We sought evidence that variation in HIV-1 CD4+ T helper epitopes might contribute to this phenomenon. To determine this, we assayed fresh peripheral blood mononuclear cells from 43 asymptomatic HIV-1+ patients for proliferative responses to HIV-1 antigens. 12 (28%) showed a positive response, and we went on to map dominant epitopes in two in iduals, to p24 Gag restricted by human histocompatibility leukocyte antigen (HLA)-DR1 and to p17 Gag restricted by HLA-DRB52c. Nine naturally occurring variants of the p24 Gag epitope were found in the proviral DNA of the in idual in whom this response was detected. All variants bound to HLA-DR1, but three of these peptides failed to stimulate a CD4+ T lymphocyte line which recognized the index sequence. Antigenic variation was also detected in the p17 Gag epitope a dominant viral variant present in the patient was well recognized by a specific CD4+ T lymphocyte line, whereas several natural mutants were not. Importantly, variants detected at both epitopes also failed to stimulate fresh uncultured cells while index peptide stimulated successfully. These results demonstrate that variant antigens arise in HIV-1+ patients which fail to stimulate the T cell antigen receptor of HLA class II–restricted lymphocytes, although the peptide epitopes are capable of being presented on the cell surface. In HIV-1 infection, naturally occurring HLA class II–restricted altered peptide ligands that fail to stimulate the circulating T lymphocyte repertoire may curtail helper responses at sites where variant viruses predominate.

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

DOI: 10.1073/PNAS.2101918118

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.

Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.

Publisher: Proceedings of the National Academy of Sciences

Date: 03-07-1995

DOI: 10.1073/PNAS.92.14.6567

Abstract: HLA-DR13 has been associated with resistance to two major infectious diseases of humans. To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position. The eluted peptides were subjected to pool sequencing or in idual peptide sequencing by tandem MS or Edman microsequencing. Sequences were obtained for 23 peptides from nine source proteins. Three pool sequences for each allele and the sequences of in idual peptides were used to define binding motifs for each allele. Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301. Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1*1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly-- Val change at position 86. These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.

Cell turnover and cell tropism in HIV-1 infection

Publisher: Elsevier BV

Date: 06-2002

DOI: 10.1016/S0966-842X(02)02370-3

Abstract: Early infection with HIV-1 is dominated by CCR5-tropic (R5, non-syncytium-inducing) viruses. The evolution of CXCR4-tropic (X4, syncytium-inducing) viruses occurs later in the infection and is associated with rapid disease progression. Here, we propose that the tropism of X4 viruses for naive CD4+ T cells is disadvantageous in early infection owing to the low ision rate of these cells. In healthy in iduals, the ision rate of memory cells is nearly ten times higher than that of naive cells and thus the memory-cell tropism of R5 viruses could account for their dominance early in infection. As the ision rate of naive T cells increases with CD4+ depletion, X4 viruses come to dominate in late disease.

Contribution of T cell receptor affinity to overall avidity for virus-specific CD8+ T cell responses.

Publisher: Proceedings of the National Academy of Sciences

Date: 08-2005

DOI: 10.1073/PNAS.0504851102

Abstract: Prior analysis has characterized the clonal characteristics of effector CD8 + T cells specific for the prominent influenza A virus nucleoprotein (NP) and acid polymerase (PA) peptides presented by H2D b . Using a single-cell approach and determination of CDR3β profiles, a limited, predominantly “public” repertoire was found for CD8 + D b NP 366 + Vβ8.3 + cells, whereas erse and “private” T cell antigen receptor (TCR)β clonotypes were typical of the CD8 + D b PA 224 + Vβ7 + response. This single-cell approach has now been used to relate the contributions of particular clonotypes (or affinities) to high-avidity TCRs, as defined by binding under conditions of limiting tetramer availability. At least by the measure of CDR3β usage, no difference could be found between total and high-avidity populations in the spectrum of TCR-pMHC affinities throughout the limited, and relatively public, CD8 + D b NP 366 + Vβ8.3 + populations. Conversely, the more even (by clone size), erse, and private CD8 + D b PA 224 + Vβ7 + response was characterized by the clear partitioning of the largest T cell clones in the high-avidity compartment. These results suggest that the relatively constrained CD8 + D b NP 366 + Vβ8.3 + set utilizes a relatively narrow range of affinities, whereas the broader CD8 + D b PA 224 + Vβ7 + response is induced at a range of TCR-pMHC affinities. Thus, whereas TCR sequence (or affinity) appears to contribute substantially to the avidity profile of erse virus-specific CD8 + populations, other mechanisms may be prominent where the TCR spectrum is more limited.

Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection

Publisher: Proceedings of the National Academy of Sciences

Date: 02-07-2018

DOI: 10.1073/PNAS.1719451115

Abstract: Epidemiological studies have shown a correlation between CMV infection and immune system aging, especially in elderly populations. It remains unclear whether CMV infection is a key driver of, or simply a factor associated with, aging of the immune system. We show that aging in the presence of lifelong CMV infection improves T cell immunity in old animals by broadening the immune response to a different pathogen. Animals that have aged with CMV are able to recruit novel T cells into these immune responses that are present in, but not utilized in, animals aging without CMV. These data squarely challenge the premise that CMV is solely detrimental to the aging of the adaptive immune system.

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.

Vaccination and Timing Influence SIV Immune Escape Viral Dynamics In Vivo

Publisher: Public Library of Science (PLoS)

Date: 25-01-2008

DOI: 10.1371/JOURNAL.PPAT.0040012

Rapid disease progression and the rate of spread of the HIV epidemic

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2001

DOI: 10.1097/00002030-200110190-00024

mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern

Publisher: American Association for the Advancement of Science (AAAS)

Date: 03-12-2021

DOI: 10.1126/SCIENCE.ABM0829

Abstract: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing severe COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding the longevity of vaccine-induced immune protection. Goel et al . examined B and T lymphocyte responses in in iduals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study of in iduals who never had SARS-CoV-2 infection compared with people who had recovered from SARS-CoV-2. Humoral and cellular immune memory was observed in vaccinated in iduals, as were functional immune responses against the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) viral variants. Analysis of T cell activity suggested that robust cellular immune memory may prevent hospitalization by limiting the development of severe disease. —PNK

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

DOI: 10.1371/JOURNAL.PPAT.1000378

Insights into the Motif Preference of APOBEC3 Enzymes

Publisher: Public Library of Science (PLoS)

Date: 31-01-2014

DOI: 10.1371/JOURNAL.PONE.0087679

Estimating the contribution of the gut to plasma viral load in early SIV infection

Publisher: Springer Science and Business Media LLC

Date: 14-10-2013

DOI: 10.1186/1742-4690-10-105

Abstract: There is significant debate about whether the gut plays a major role in viral replication and pathology in HIV infection. Here we aimed to estimate the contribution of the gut to the total virus observed in plasma, by comparing the frequency of different viral mutants in plasma and gut in SIV infection. We found that the maximum contribution of gut to plasma viral load estimated from rectal biopsy at day 28 post-infection had a median of 10%. The estimated values for in idual animals ranged from nearly 100% to % in 4/14 animals. Importantly, these are maximum estimates, so that a value of 90%, for ex le, means that the real contribution may be anything between 0 and 90%, just not higher than 90%. We also studied the contribution of gut at the peak of plasma viral load (day 14). However, since there was very little escape in most animals at this time point, we could only estimate the maximal contribution of gut in 4 animals, in two of which it was %. The role of the gut in HIV is a controversial area, with many suggesting that it plays a dominant role in driving early infection. Our analysis suggests that, at least by day 28 post-infection, the gut is not contributing greatly to the plasma viral load.

Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection

Publisher: Proceedings of the National Academy of Sciences

Date: 03-07-2017

DOI: 10.1073/PNAS.1618939114

Abstract: Adaptive immunity to Plasmodium falciparum takes years to develop in endemic regions, leaving young children vulnerable to high parasite burdens and severe malaria. Host innate immune responses clearly occur during infection and may control parasite numbers in nonimmune in iduals, for ex le by accelerating parasite removal from circulation. However, evidence of whether and how this occurs in vivo remains sparse. We set out to measure host removal of parasites during acute blood-stage Plasmodium infection in mice. However, rather than being removed more rapidly, parasites unexpectedly persisted in circulation. Persistence resulted from host-dependent slowing of parasite maturation. Thus Plasmodium maturation within red blood cells does not occur at a constant rate in vivo and can be influenced by the host itself.

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.

Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations

Publisher: The American Association of Immunologists

Date: 12-2014

DOI: 10.4049/JIMMUNOL.1401017

Abstract: Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2Kd epitope elicited high-avidity CD8 T cell populations with architecturally erse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2Dd epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2Dd specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.

Increased Stability and Limited Proliferation of CD4 ⁺ Central Memory T Cells Differentiate Nonprogressive Simian Immunodeficiency Virus (SIV) Infection of Sooty Man

Publisher: American Society for Microbiology

Date: 15-04-2014

DOI: 10.1128/JVI.03515-13

Abstract: Depletion of CD4 + central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4 + TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4 + TCM cells of RMs. Whether this relative protection from infection translates into increased stability of CD4 + TCM cells in natural versus nonnatural hosts has not yet been determined. Here we compared, both cross-sectionally and longitudinally, the levels of CD4 + TCM cells in a large cohort of SMs and RMs and the association between CD4 + TCM levels and the main virologic and immunologic markers of disease progression. Consistent with their lower susceptibility to infection, CD4 + TCM cells of SIV-infected SMs are lost with kinetics 20 times slower than those of SIV-infected RMs. Remarkably, the estimated length of time of SIV infection needed for CD4 + TCM cells to fall to half of their initial levels is months for RMs but years for SMs. Furthermore, the fraction of proliferating CD4 + TCM cells is significantly lower in SIV-infected SMs than in SIV-infected RMs, and the extent of CD4 + TCM cell proliferation is associated positively with CD4 + T cell levels in SIV-infected SMs but negatively with CD4 + T cell levels in SIV-infected RMs. Collectively, these findings identify increased stability and maintenance of the prohomeostatic role of CD4 + TCM cells as features distinguishing nonprogressive from progressive SIV infections and support the hypothesis of a direct mechanistic link between the loss of CD4 + TCM cells and disease progression. IMPORTANCE Comparison of the immunologic effects of simian immunodeficiency virus (SIV) infection on rhesus macaques (RMs), a species characterized by progression to AIDS, and natural host sooty mangabeys (SMs), a species which remains AIDS free, has become a useful tool for identifying mechanisms of human immunodeficiency virus (HIV) disease progression. One such distinguishing feature is that CD4 + central memory T (TCM) cells in SIV-infected SMs are less infected than the same cells in RMs. Here we investigated whether lower levels of infection in SMs translate into a better-preserved CD4 + TCM compartment. We found that the CD4 + TCM compartment is significantly more stable in SIV-infected SMs. Likely to compensate for this cell loss, we also found that CD4 + TCM cells increase their level of proliferation upon SIV infection in RMs but not in SMs, which mechanistically supports their preferential infectivity. Our study provides new insights into the importance of long-term maintenance of CD4 + TCM homeostasis during HIV/SIV infection.

Identifying recombination hot spots in the HIV-1 genome

Publisher: American Society for Microbiology

Date: 03-2014

DOI: 10.1128/JVI.03014-13

Abstract: HIV-1 infection is characterized by the rapid generation of genetic ersity that facilitates viral escape from immune selection and antiretroviral therapy. Despite recombination's crucial role in viral ersity and evolution, little is known about the genomic factors that influence recombination between highly similar genomes. In this study, we use a minimally modified full-length HIV-1 genome and high-throughput sequence analysis to study recombination in gag and pol in T cells. We find that recombination is favored at a number of recombination hot spots, where recombination occurs six times more frequently than at corresponding cold spots. Interestingly, these hot spots occur near important features of the HIV-1 genome but do not occur at sites immediately around protease inhibitor or reverse transcriptase inhibitor drug resistance mutations. We show that the recombination hot and cold spots are consistent across five blood donors and are independent of coreceptor-mediated entry. Finally, we check common experimental confounders and find that these are not driving the location of recombination hot spots. This is the first study to identify the location of recombination hot spots between two similar viral genomes with great statistical power and under conditions that closely reflect natural recombination events among HIV-1 quasispecies. IMPORTANCE The ability of HIV-1 to evade the immune system and antiretroviral therapy depends on genetic ersity within the viral quasispecies. Retroviral recombination is an important mechanism that helps to generate and maintain this genetic ersity, but little is known about how recombination rates vary within the HIV-1 genome. We measured recombination rates in gag and pol and identified recombination hot and cold spots, demonstrating that recombination is not random but depends on the underlying gene sequence. The strength and location of these recombination hot and cold spots can be used to improve models of viral dynamics and evolution, which will be useful for the design of robust antiretroviral therapies.

Diversity of the CD8+ T Cell Repertoire Elicited against an Immunodominant Epitope Does Not Depend on the Context of Infection

Publisher: The American Association of Immunologists

Date: 15-03-2010

DOI: 10.4049/JIMMUNOL.0903493

Abstract: The ersity of the pathogen-specific T cell repertoire is believed to be important in allowing recognition of different pathogen epitopes and their variants and thereby reducing the opportunities for mutation-driven pathogen escape. However, the extent to which the TCR repertoire can be manipulated by different vaccine strategies so as to obtain broad ersity and optimal protection is incompletely understood. We have investigated the influence of the infectious/inflammatory context on the TCR ersity of the CD8+ T cell response specific for the immunodominant epitope in C57BL/6 mice, derived from glycoprotein B of HSV-1. To that effect, we compared TCR V segment utilization, CDR3 length, and sequence ersity of the response to natural HSV-1 infection with those elicited by either Listeria monocytogenes or vaccinia virus expressing the immunodominant epitope in C57BL/6 mice. We demonstrate that although the type of infection in which the epitope was encountered can influence the magnitude of the CD8+ T cell responses, TCR β-chain repertoires did not significantly differ among the three infections. These results suggest that widely different live vaccine vectors may have little impact upon the ersity of the induced CTL response, which has important implications for the design of live CTL vaccine strategies against acute and chronic infections.

Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy

Publisher: Public Library of Science (PLoS)

Date: 04-05-2017

DOI: 10.1371/JOURNAL.PPAT.1006359

Division‐linked differentiation can account for CD8⁺ T‐cell phenotype in vivo

Publisher: Wiley

Date: 2009

DOI: 10.1002/EJI.200838554

Abstract: The CD8(+) T-cell response to infection involves a large initial expansion in the numbers of responding cells, accompanied by differentiation of these cells. Expression of the adhesion molecule CD62L is high on naïve cells and rapidly downregulated on the surface of the majority (approximately 90%) of cells during the 'effector' phase of acute infection. Adoptive transfer studies have been used to study differentiation in this system however, relatively little work has investigated the phenotype of cells in the endogenous repertoire. We demonstrate that the extent of CD62L down-regulation is positively correlated with clone size in vivo, consistent with ision-linked differentiation of responding cells. Other features of the endogenous CD62L(hi) and CD62L(lo) repertoire are that the CD62L(lo) repertoire is less erse than the CD62L(hi) repertoire and represents a subset of clonotypes found in the CD62L(hi) repertoire. To test whether these observations are compatible with a mechanism of ision-linked differentiation, we developed a mathematical model, where there is a probability of CD62L down-regulation associated with cell ision. Comparison of model results with experimental data suggests that ision-linked differentiation provides a simple mechanism to explain the relationship between clone size and phenotype of CD8(+) T cells during acute infection.

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).

Understanding the Relationship BetweenPlasmodium falciparumGrowth Rate and Multiplicity of Infection

Publisher: Oxford University Press (OUP)

Date: 09-10-2014

DOI: 10.1093/INFDIS/JIU561

Abstract: Natural infections with Plasmodium falciparum are often composed of multiple concurrent genetically distinct parasite clones. Such multiclonal infections are more common in areas of high transmission, and the frequency of multiclonal infection also varies with age. A number of studies have suggested that multiclonal infection predicts the risk of subsequent clinical malaria. The multiplicity of infection is determined by the rate of new infections, the number of clones inoculated at each mosquito bite, and the duration of infections. Here, we used a mathematical modeling approach to understand how variation in the growth rate of blood-stage parasites affects the observed multiplicity of infection (MOI), as well as the relationship between the MOI and the risk of subsequent malaria. We then analyzed data from a study of multiclonal infection and malaria in an malaria-endemic area in Tanzania and show that the proportion of multiclonal infections varies with age and that the observed relationship between multiclonal infection and subsequent clinical events can be explained by a reduction in blood-stage parasite growth with age in this population.

The MHC in Host-Pathogen Evolution

Publisher: Springer US

Date: 1996

DOI: 10.1007/978-1-4684-6462-7_15

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.

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.

Modeling the dynamics of Plasmodium vivax infection and hypnozoite reactivation in vivo.

Publisher: Public Library of Science (PLoS)

Date: 17-03-2015

DOI: 10.1371/JOURNAL.PNTD.0003595

Narrowed TCR diversity for immunised mice challenged with recombinant influenza A-HIV Env311-320 virus

Publisher: Elsevier BV

Date: 11-2009

DOI: 10.1016/J.VACCINE.2009.08.079

Abstract: Understanding CD8+ T cell responses generated by live virus vectors is critical for the rational design of next generation HIV CTL-based vaccines. We used recombinant influenza viruses expressing the HIV Env(311-320) peptide in the neuraminidase stalk to study response magnitude, cytokine production and repertoire ersity for the elicited CD8+ D(d)Env(311) CTL set. The insertion of the CD8+ D(d)Env(311) epitope into the NA stalk resulted in a decrease in viral fitness that was reflected in lower lung viral titres. While not affecting the magnitude of endogenous primary influenza-specific responses, the introduction of the D(d)Env(311) CD8+ T cell epitope altered the hierarchy of responses following secondary challenge. The CD8+ K(d)NP(147) response increased 9-fold in the spleen following secondary infection whereas the CD8+ D(d)Env(311) response increased 15-fold in the spleen. Moreover, this study is the first to describe narrowing of CD8+ TCR repertoire ersity in the context of an evolving secondary immune response against influenza A virus. Analysis of Vbeta bias for CD8+ D(d)Env(311) T cell responses showed a narrowing of CD8+ Vbeta8.1/8.2 D(d)Env(311) TCR repertoire ersity. This work further emphasizes the importance of understanding vaccine-induced CD8+ T cell responses.

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

DOI: 10.1172/JCI.INSIGHT.167157

Contemporaneous fluctuations in T cell responses to persistent herpes virus infections

Publisher: Wiley

Date: 16-12-2004

DOI: 10.1002/EJI.200425548

Abstract: The classical paradigm for T cell dynamics suggests that the resolution of a primary acute virus infection is followed by the generation of a long-lived pool of memory T cells that is thought to be highly stable. Very limited alteration in this repertoire is expected until the immune system is re-challenged by reactivation of latent viruses or by cross-reactive pathogens. Contradicting this view, we show here that the T cell repertoire specific for two different latent herpes viruses in the peripheral blood displayed significant contemporaneous co-fluctuations of virus-specific CD8(+) T cells. The coordinated responses to two different viruses suggest that the fluctuations within the T cell repertoire may be driven by sub-clinical viral reactivation or a more generalized 'bystander' effect. The later contention was supported by the observation that, while absolute number of CD3(+) T cells and their subsets and also the cell surface phenotype of antigen-specific T cells remained relatively constant, a loss of CD62L expression in the total CD8(+) T cell population was coincident with the expansion of tetramer-positive virus-specific T cells. This study demonstrates that the dynamic process of T cell expansion and contractions in persistent viral infections is not limited to the acute phase of infection, but also continues during the latent phase of infection.

Early Priming Minimizes the Age-Related Immune Compromise of CD8+ T Cell Diversity and Function

Publisher: Public Library of Science (PLoS)

Date: 23-02-2012

DOI: 10.1371/JOURNAL.PPAT.1002544

Killer T cells regulate antigen presentation for early expansion of memory, but not naive, CD8⁺ T cell

Publisher: Proceedings of the National Academy of Sciences

Date: 10-04-2007

DOI: 10.1073/PNAS.0609990104

Abstract: Antigen presentation within the lymph node draining a site of infection is crucial for initiation of cytotoxic T cell responses. Precisely how this antigen presentation regulates T cell expansion in vivo is unclear. Here, we show that, in primary infection, antigen presentation peaks ≈3 days postinfection and then slowly decays until day 12. This prolonged antigen presentation is required for optimal expansion of naive CD8 + T cells, because early ablation of dendritic cells reduces the later CD8 + T cell response. Antigen presentation during secondary infection was 10-fold lower in magnitude and largely terminated by day 4 postinfection. Expansion of memory, but not naive, antigen-specific T cells was tightly controlled by perforin-dependent cytolysis of antigen-presenting cells. The ability of the memory T cells to remove antigen-presenting cells provides a negative-feedback loop to directly limit the duration of antigen presentation in vivo .

Los Alamos National Laboratory

Location: United States of America

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University Of Oxford

Location: United Kingdom of Great Britain and Northern Ireland

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University Of Sydney

Location: Australia

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UNSW Australia

Location: Australia

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UNSW Sydney

Location: Australia

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St Vincent's Hospital Sydney

Location: Australia

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Discovery Projects - Grant ID: DP0987339

Start Date: 2009

End Date: 12-2012

Amount: $510,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0771340

Start Date: 2007

End Date: 04-2011

Amount: $396,000.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR0354592

Start Date: 02-2004

End Date: 11-2004

Amount: $20,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP1095581

Start Date: 2010

End Date: 12-2016

Amount: $650,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP210103114

Start Date: 05-2021

End Date: 05-2024

Amount: $676,622.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100149

Start Date: 12-2014

End Date: 06-2015

Amount: $300,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180103875

Start Date: 06-2018

End Date: 12-2021

Amount: $462,710.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP120100064

Start Date: 2012

End Date: 05-2015

Amount: $300,000.00

Funder: Australian Research Council