ORCID Profile
0000-0002-1906-6945
Current Organisation
University of Melbourne
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.CLIM.2009.07.012
Abstract: Donor cell microchimerism induces tolerance in animal models and may increase graft survival in man. Since dendritic cells (DC) are critical for induction of both tolerance and alloreactivity we developed a method to quantitate microchimerism in donor DC and non-DC in peripheral blood mononuclear cells (PBMC) after lung transplantation. Longitudinal analysis of donor cell microchimerism in eleven sex mismatched lung transplant recipients (LTR) up to 12 months post-transplant used Y chromosome based real-time PCR on sorted cells. Total DC or a proportion of DC subsets in PBMC did not change but there were heterogeneous and dynamic changes in microchimerism in DC and non-DC. Analysis of changes in DC using a mixed model analysis showed significantly less reduction in DC compared to non-DC over time (0.49, p=0.001). Preferential DC persistence compared to non-DC may indicate tolerance induction but future studies are required to determine if DC microchimerism after transplantation affects clinical outcomes.
Publisher: Public Library of Science (PLoS)
Date: 13-11-2014
Publisher: Springer Science and Business Media LLC
Date: 23-09-2002
DOI: 10.1038/NI841
Publisher: Oxford University Press (OUP)
Date: 30-09-2010
DOI: 10.1189/JLB.0610371
Abstract: Measurement of NK cell cytolytic activity in the setting of chronic viral infection is important for determining viral pathogenicity. Mobilization of LAMP-1 (CD107a) to the NK cell surface is a surrogate marker for cytotoxic granule release and hence, NK cell cytotoxicity. We have developed a convenient, rapid, whole blood flow cytometric assay for measuring CD107a mobilization in response to CD16 cross-linking, a surrogate for NK cell ADCC activity ex vivo, which can be performed using small volumes of patient whole blood. Using this assay, we show that CD107a mobilization, in response to CD16 cross-linking, is triggered in CD56dim but not CD56bright NK cells, requiring Syk/Zap70 tyrosine kinase activity, and that there is a significant correlation between CD107a mobilization and pSyk/Zap70 in response to CD16 cross-linking. We compared whole blood from treatment-naïve, HIV-infected patients with age- and sex-matched HIV-uninfected control subjects and found a significant reduction in CD16-dependent pSyk/Zap70 (median=32.7% compared with 67.8% P=0.0002) and CD107a mobilization (median=9.72% compared with 32.9% P=0.046) in NK cells. Reduction of both correlated strongly with reduced CD16 surface expression on NK cells of HIV-infected in iduals (P& .01). These data suggest that ADCC is inhibited in NK cells from therapy-naïve, HIV-infected in iduals at the level of early events in CD16 signal transduction, associated with low CD16R expression, and our method is a useful and reliable tool to detect pathological defects in NK cell degranulation.
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0165-2478(94)90178-3
Abstract: Dendritic cells (DC) from human and mouse thymus were compared. DC from both sources were isolated by digestion with collagenase, disruption of cellular complexes with a chelating agent, selection of light density cells, immunomagnetic bead depletion of other cell types (without depletion with anti-CD4 or anti-CD8) and finally sorting for cells expressing high levels of class II MHC. Yields of DC from human and mouse thymus were comparable (around 1 DC/10(3) thymocytes), they displayed similar DC morphology, and both showed strong expression of CD11c. DC from the human thymus all expressed very high levels of CD4 but low levels of CD8. In contrast, DC from the mouse thymus expressed high levels of CD8 but only low levels of CD4. Human thymic DC were also substantially larger than mouse thymic DC. The biological significance of CD4 and CD8 expression by DC is discussed in view of this major species difference and the possibility that human thymic DC may be targets for HIV infection.
Publisher: American Society of Hematology
Date: 15-07-2003
DOI: 10.1182/BLOOD-2002-12-3745
Abstract: Dendritic cells (DCs) are specialized antigen-presenting cells residing in tissues, from which they take up antigen. Activated DCs migrate through chemokine gradients from sites of inflammation to lymph nodes to stimulate T cells. At sites of inflammation, nucleotides, such as adenosine triphosphate (ATP), are released by activated or dying cells and can function as signaling molecules through P2 receptors (P2Rs). We investigated P2R expression in different DC populations and the effect of nucleotides on chemokine-directed migration. Exposure of monocyte-derived DCs (MoDCs) and CD1a+ dermal DCs to gradients of ATP inhibited their migratory capacity in a dose-dependent manner. Studies using P2R agonists and antagonists implicated signaling through the P2Y11R. On maturation, MoDCs down-regulated P2Y11R expression and were less sensitive to ATP-mediated inhibition of migration. In contrast, ATP did not inhibit the migration of CD1c+ peripheral blood (PB) DCs or interleukin-3 receptor-positive (IL-3R+) plasmacytoid DCs. Although all 4 DC populations expressed mRNA for P2Y11R, calcium-flux studies showed that blood DC types were unresponsive to P2Y11R agonists. In conclusion, DCs use distinct subtypes of P2R. The formation of ATP gradients at sites of inflammation may transiently inhibit the migration of local DCs, thus prolonging the time of antigen encounter. P2R inhibition may represent a new strategy to improve the migration of antigen-loaded DCs from the vaccination site to lymph nodes.
Publisher: Public Library of Science (PLoS)
Date: 28-02-2020
Publisher: American Society for Microbiology
Date: 07-2018
DOI: 10.1128/JVI.02225-17
Abstract: HIV infection requires lifelong antiretroviral therapy because of the persistence of latently infected CD4 + T cells. The induction of virus expression from latently infected cells occurs following T cell receptor (TCR) activation, but not all latently infected cells respond to TCR stimulation. We compared two models of latently infected cells using an enhanced green fluorescent protein (EGFP) reporter virus to infect CCL19-treated resting CD4 + (rCD4 + ) T cells (preactivation latency) or activated CD4 + T cells that returned to a resting state (postactivation latency). We isolated latently infected cells by sorting for EGFP-negative (EGFP − ) cells after infection. These cells were cultured with antivirals and stimulated with anti-CD3/anti-CD28, mitogens, and latency-reversing agents (LRAs) and cocultured with monocytes and anti-CD3. Spontaneous EGFP expression was more frequent in postactivation than in preactivation latency. Stimulation of latently infected cells with monocytes/anti-CD3 resulted in an increase in EGFP expression compared to that for unstimulated controls using the preactivation latency model but led to a reduction in EGFP expression in the postactivation latency model. The reduced EGFP expression was not associated with reductions in the levels of viral DNA or T cell proliferation but depended on direct contact between monocytes and T cells. Monocytes added to the postactivation latency model during the establishment of latency reduced spontaneous virus expression, suggesting that monocyte-T cell interactions at an early time point postinfection can maintain HIV latency. This direct comparison of pre- and postactivation latency suggests that effective strategies needed to reverse latency will depend on how latency is established. IMPORTANCE One strategy being evaluated to eliminate latently infected cells that persist in HIV-infected in iduals on antiretroviral therapy (ART) is to activate HIV expression or production with the goal of inducing virus-mediated cytolysis or immune-mediated clearance of infected cells. The gold standard for the activation of latent virus is T cell receptor stimulation with anti-CD3/anti-CD28. However, this stimulus activates only a small proportion of latently infected cells. We show clear differences in the responses of latently infected cells to activating stimuli based on how latent infection is established, an observation that may potentially explain the persistence of noninduced intact proviruses in HIV-infected in iduals on ART.
Publisher: Oxford University Press (OUP)
Date: 28-02-2014
Abstract: We investigated the relationship between microbial translocation, immune activation, and liver disease in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection. Lipopolysaccharide (LPS), soluble CD14, CXCL10, and CCL-2 levels were elevated in patients with HIV/HBV coinfection. Levels of LPS, soluble CD14, and CCL-2 declined following receipt of HBV-active combination antiretroviral therapy (cART), but the CXCL10 level remained elevated. No markers were associated with liver disease severity on liver biopsy (n = 96), but CXCL10, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α, and interferon γ (IFN-γ) were all associated with elevated liver enzyme levels during receipt of HBV-active cART. Stimulation of hepatocyte cell lines in vitro with IFN-γ and LPS induced a profound synergistic increase in the production of CXCL10. LPS may contribute to liver disease via stimulating persistent production of CXCL10.
Publisher: American Society of Hematology
Date: 15-03-2004
DOI: 10.1182/BLOOD-2003-09-3129
Abstract: HIV-1 subverts antigen processing in dendritic cells (DCs) resulting in viral uptake, infection, and transfer to T cells. Although DCs bound monomeric gp120 and HIV-1 similarly, virus rarely colocalized with endolysosomal markers, unlike gp120, suggesting HIV-1 alters endolysosomal trafficking. Virus within DC intracellular compartments rapidly moved to DC-CD4+ lymphocyte synapses when introduced to CD4+ lymphocyte cultures. Although viral harboring and transfer from nonlysosomal compartments was transient, given DC-associated virus protein, nucleic acids, and infectious HIV-1 transfer to CD4+, lymphocytes decayed within 24 hours. However a second long-term transfer phase was apparent in immature DCs after 48 hours as a zidovudine-sensitive rise in proviral DNA. Therefore, DCs transfer HIV-1 to CD4+ lymphocytes in 2 distinct phases. Immature and mature DCs first ert virus from the endolysosomal pathway to the DC–T-cell synapse. Secondly, the later transfer phase from immature DCs is through de novo HIV-1 production. Thus, the controversy of DCs being infected or not infected for the mechanics of viral transfer to CD4+ lymphocytes can be addressed as a function of time.
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: Elsevier BV
Date: 07-1975
Publisher: Springer Science and Business Media LLC
Date: 05-03-2011
DOI: 10.1007/S11481-011-9268-5
Abstract: Intracellular signaling events are signposts of biological processes, which govern the direction and action of biological activities. Through millions of years of evolution, pathogens, such as viruses, have evolved to hijack host cell machinery to infect their targets and are therefore dependent on host cell signaling for replication. This review will detail our current understanding of the signaling events that are important for the early steps of HIV-1 replication. More specifically, the therapeutic potential of signaling events associated with chemokine coreceptors, virus entry, viral synapses, and post-entry processes will be discussed. We argue that these pathways may represent novel targets for antiviral therapy.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-09-2010
Abstract: Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4 + T cells. We now show that HIV-1 latency can be established in resting CD4 + T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4 + T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4 + T cells during normal chemokine-directed recirculation of CD4 + T cells between blood and tissue.
Publisher: Oxford University Press (OUP)
Date: 24-01-2006
DOI: 10.1189/JLB.0905522
Abstract: Peripheral blood monocyte subpopulations have been reported and can give rise to erse, differentiated phenotypes. A subpopulation(s) of human monocytes can proliferate in vitro in response to macrophage-colony stimulating factor (M-CSF or CSF-1). This population, termed the proliferative monocyte (PM), is presumably less mature than other monocytes however, it has not been defined further. Previous studies monitoring the frequency of the slowly cycling PM from different donors indicated that the assay for their reproducible measurement required improvement. We demonstrate that for optimal PM detection, high 5-bromo-2′-deoxyuridine concentrations are required over a delayed and wide time-frame. Surface marker phenotyping by flow cytometry showed that freshly isolated PM are CD14+ and could be distinguished from two other human monocyte subpopulations, namely, the CD14loCD16+ and CD14loCD64– subsets. PM express relatively high levels of CD64 and CD33 but have relatively low CD13 expression they are also c-Fms+ and human leukocyte antigen-DR+. Labeling with carboxyfluorescein diacetate succinimidyl ester (CFSE) enabled the estimation of the number of PM isions over time. Following CFSE labeling and culture, PM were sorted from the nonproliferating population and shown to have a distinctive, spindle-shaped morphology and higher capacity to form multinucleated, tartrate-resistant acid phosphatase+ cells in the presence of M-CSF and receptor activator of nuclear factor-κB ligand. The phenotype and properties of the PM subpopulation were examined as a prelude to determining its role in disease using methods that can be applied to clarify human monocyte heterogeneity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2010
Publisher: Wiley
Date: 12-2019
DOI: 10.1002/JIA2.25425
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-10-2007
DOI: 10.1002/HEP.21844
Abstract: Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from in iduals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8(+) T cells from the liver producing IL-10 (P = 0.044), primarily in hepatitis B e antigen positive (HBeAg(+)) in iduals. A positive correlation resulted between the magnitude of HBV-specific TNF-alpha(+) CD4(+) T cells in the liver and the degree of liver inflammation and fibrosis (P = 0.002 and P = 0.006, respectively). The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.
Publisher: Oxford University Press (OUP)
Date: 09-04-2013
DOI: 10.1189/JLB.0812391
Abstract: Tetraspanins are differentially expressed in monocyte subsets and modified by inflammatory situations including HIV-1 infection. Tetraspanins are a family of membrane-organizing proteins that mediate erse functions. Little is known of their expression or function in myeloid cells. Here, expression of CD9, CD53, CD63, and CD81, tetraspanins that have been implicated in HIV-1 pathogenesis, were characterized in normal monocyte subsets, in MDM, and in HIV-1-infected donors. We show that tetraspanins are expressed differentially by monocyte subsets, with higher CD9 and CD63 and lower CD53 and CD81 levels on CD14++CD16− monocytes compared with CD14++CD16+ and CD14+CD16++ subsets. Maturation of monocytes resulted in increased CD9 expression and apparent relocation of CD63 and CD53 from surface to intracellular membranes. Expression was modulated by cytokines, and CD9 was a marker of anti-inflammatory and CD53 a marker of proinflammatory MDM. Tetraspanin expression on monocyte subsets from HIV-1-infected donors receiving antiretroviral therapy was unchanged compared with that in uninfected donors. However, CD53 expression was inversely correlated with viral load in HIV-1-infected donors not on therapy. This study is the first to comprehensively characterize tetraspanin expression on monocyte subsets and macrophages in health and during HIV-1 infection. It demonstrates regulation of tetraspanin expression by cytokines, and CD53 expression as a novel correlate of a proinflammatory phenotype. This paper characterizes tetraspanins in myeloid cells and shows that tetraspanins are expressed differentially in monocyte subsets and are modified in inflammatory conditions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1097/00002030-200501030-00014
Abstract: Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.
Publisher: Elsevier BV
Date: 06-1990
DOI: 10.1016/0140-6736(90)91418-A
Abstract: A questionnaire was used to assess general practitioners' knowledge of handicaps and service use among disabled patients in a group practice. The disabled patients were identified by a postal screening questionnaire. Sixty-eight were subsequently interviewed to assess the severity of restrictions on their activities and to collect information about informal support and use of community or hospital services. The areas of life in which the disabled were most affected by their medical conditions were sleep and rest, household management, emotion and mood. Relatives assisted the disabled considerably with all daily activities but more help was requested. Most disabled patients had consulted their general practitioner or attended casualty and outpatient clinics, but only a minority had used other community services. Prescription of drugs was considered the most important service the doctor provided. A second questionnaire, which the general practitioners completed with the help of their records, revealed that they knew of only 50 per cent of the difficulties with daily living reported by the disabled and even less of the aids, appliances and services used. A better awareness of these facilities among general practitioners might lead to a more effective distribution of resources among their patients.
Publisher: Public Library of Science (PLoS)
Date: 25-06-2015
Publisher: Wiley
Date: 06-2001
DOI: 10.1046/J.1440-1711.2001.01011.X
Abstract: Blood dendritic cells (DC) efficiently carry HIV-1 and transmit infection to CD4+ T cells in the absence of productive infection of the APC. Fluorescent latex beads were used to define the endocytic pathways that may contribute to this non-infectious pathway of virus carriage. Beads between 14 nm and 2300 nm in diameter were taken up by uncultured blood DC, but uptake of beads larger than 280 nm was much reduced in the DC compared to monocytes. After culture, there was a reduction in bead carriage in DC compared to monocytes. In the DC, beads were found as small aggregates in class II containing compartments or as single beads just below the cell surface. Beads accumulated in monocytes as aggregates in class II negative compartments. Bead recycling occurred in DC, but not in the fresh or cultured monocytes. Electron microscopy of HIV-1-pulsed DC cultured with CD4+ T cells showed accumulation of apoptotic debris and virions within endosomes in the DC. The peripheral location and recycling of endocytosed material in DC provides a pathway for virion transfer from DC to T cells that does not occur in monocytes.
Publisher: The American Association of Immunologists
Date: 15-05-2007
DOI: 10.4049/JIMMUNOL.178.10.6581
Abstract: HIV-1 persists in peripheral blood monocytes in in iduals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected in iduals on HAART when compared with the majority of monocytes (CD14highCD16−). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16− monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2019
DOI: 10.1038/S41467-019-10697-W
Abstract: Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c + dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c + DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33 low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.
Publisher: BMJ
Date: 11-06-1988
DOI: 10.1136/BMJ.296.6637.1627
Abstract: The hypothesis that complement is important in the host response to human immunodeficiency virus (HIV) was tested. Complement C4 and Bf allotypes were determined in 26 patients who fulfilled the diagnostic criteria for persistent generalised lymphadenopathy due to HIV, 72 homosexuals who were negative for antibody to HIV, and 185 control subjects drawn from the local population. HLA-A, B, and DR were also typed and the phenotypes examined for the presence of supratypes and C4BQ0. Eleven patients (42%) had C4B null alleles compared with only 13 (18%) homosexuals who were negative for antibody and 28 (15%) controls. From estimates of gene frequencies the difference between the patients with lymphadenopathy and the controls was significant after conservative correction. In the patients only a minority (six) of the C4B null alleles were contained within ancestral haplotypes. Together with the fact that C4 null alleles result in partial deficiency of C4, this finding suggests that products of complement genes are important in infection with HIV or its consequences, or both. A role is proposed for complement and Fc receptors.
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.
Publisher: Wiley
Date: 06-02-2013
Abstract: Bone marrow stromal cell-2 (BST-2) has major roles in viral tethering and modulation of interferon production. Here we investigate BST-2 as a receptor for the delivery of antigen to dendritic cells (DCs). We show that BST-2 is expressed by a panel of mouse and human DC subsets, particularly under inflammatory conditions. The outcome of delivering antigen to BST-2 expressed by steady state and activated plasmacytoid DC (pDC) or conventional CD8(+) and CD8(-) DCs was determined. T-cell responses were measured for both MHC class I (MHCI) and MHC class II (MHCII) antigen presentation pathways in vitro. Delivering antigen via BST-2 was compared with that via receptors DEC205 or Siglec-H. We show that despite a higher antigen load and faster receptor internalisation, when antigen is delivered to steady state or activated pDC via BST-2, BST-2-targeted activated conventional DCs present antigen more efficiently. Relative to DEC205, BST-2 was inferior in its capacity to deliver antigen to the MHCI cross-presentation pathway. In contrast, BST-2 was superior to Siglec-H at initiating either MHCI or MHCII antigen presentation. In summary, BST-2 is a useful receptor to target with antigen, given its broad expression pattern and ability to access both MHCI and MHCII presentation pathways with relative efficiency.
Publisher: Springer Science and Business Media LLC
Date: 2007
Publisher: Informa UK Limited
Date: 04-2004
Publisher: Springer Science and Business Media LLC
Date: 03-06-2011
Abstract: HIV-1 infection of the thymus contributes to the defective regeneration and loss of CD4 + T cells in HIV-1-infected in iduals. As thymic dendritic cells (DC) are permissive to infection by HIV-1, we examined the ability of thymic DC to enhance infection of thymocytes which may contribute to the overall depletion of CD4 + T cells. We compared productive infection in isolated human thymic and blood CD11c + myeloid DC (mDC) and CD123 + plasmacytoid DC (pDC) using enhanced green fluorescent protein (EGFP) CCR5 (R5)-tropic NL(AD8) and CXCR4 (X4)-tropic NL4-3 HIV-1 reporter viruses. Transfer of productive HIV-1 infection from thymic mDC and pDC was determined by culturing these DC subsets either alone or with sorted thymocytes. Productive infection was observed in both thymic pDC and mDC following exposure to R5 HIV-1 and X4 HIV-1. Thymic pDC were more frequently productively infected by both R5 and X4 HIV-1 than thymic mDC (p = 0.03 n = 6). Thymic pDC efficiently transferred productive R5 HIV-1 infection to both CD3 hi (p = 0.01 mean fold increase of 6.5 n = 6) and CD3 lo thymocytes (mean fold increase of 1.6 n = 2). In comparison, transfer of productive infection by thymic mDC was not observed for either X4 or R5 HIV-1. The capacity of thymic pDC to efficiently transfer R5 HIV-1 to both mature and immature thymocytes that are otherwise refractory to R5 virus may represent a pathway to early infection and impaired production of thymocytes and CD4 + T cells in HIV-1-infected in iduals.
Publisher: Elsevier BV
Date: 04-1990
DOI: 10.1016/0090-1229(90)90070-7
Abstract: Twenty-four patients with various degrees of human immunodeficiency virus (HIV)-associated immunodeficiency were treated with zidovudine for up to 6 months. Nineteen of these patients had persistent depression of delayed-type hypersensitivity (DTH) responses prior to commencing therapy. In 11 of these 19 patients (58%) there was sustained improvement of DTH responses with the maximal effect occurring at approximately 3 months after therapy was started. DTH declined after 3 months but remained significantly higher than baseline at 6 months. Patients who did not have a sustained increase in DTH responses had more severe disease than those that did. Blood CD4+ T-cell counts increased in the majority of patients on zidovudine therapy, but varied independently of DTH responses. Epidermal Langerhans cell density was lower in HIV-infected patients than controls but also varied independently of DTH responses before and after zidovudine therapy. We suggest that sequential measurement of DTH responses is a valuable means of monitoring the restoration of cell-mediated immune responses by zidovudine in some HIV-infected patients. Our findings also demonstrate the need to define the processes involved in the restoration of DTH responses as this may lead to new approaches to the therapeutic manipulation of cell-mediated immune responses in HIV-infected patients.
Publisher: Forum: Carbohydrates Coming of Age
Date: 2002
DOI: 10.4052/TIGG.14.255
Publisher: Wiley
Date: 09-09-2003
DOI: 10.1034/J.1600-0625.2003.00078.X
Abstract: Langerhans' cells (LC) of skin are CD4 expressing, dendritic, antigen-presenting cells, that are essential for activation of primary immune responses and are productively infected by HIV. We have shown previously that lymphocytes and monocytes express CD4 both as monomers and covalently linked homodimers. In those cells the 55-kDa monomer structure predominates. LC in un-fractionated human epidermal cell (EC) suspension also expresses both forms of CD4, but in EC the dimer form is predominant. Because isolation of LC into single cell suspension by trypsin, as is routinely used for LC isolation, degrades CD4, a systematic study for an alternate procedure for LC isolation was performed. Thus it was found that collagenase blend F treatment can efficiently release LC into suspension, under conditions of only minimal degradation of control soluble recombinant CD4 or CEM-T4 or THP-1 cell CD4, or importantly of LC surface CD4. SDS-PAGE immunoblotting of purified LC extracted from EC by collagenase confirmed CD4 structure as predominantly 110-kDa dimers, with only minimal 55-kDa monomers. The suitability of LC prepared thus for functional studies was demonstrated with binding of functional ligand HIV gp120. It remains to be determined, however, why tissue embedded LC express mainly CD4 dimers, but single-celled blood lymphocytes and monocytes mainly monomers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2013
Publisher: Hindawi Limited
Date: 22-07-2010
DOI: 10.1002/HUMU.21321
Abstract: Human Toll-like receptors (TLRs) TLR7, TLR8, and TLR9 are important immune sensors of foreign nucleic acids encountered by phagocytes. Although there is growing evidence implicating TLR7 and TLR9 in the detection of intracellular pathogenic bacteria, characterization of such a role for TLR8 is currently lacking. A recent genetic study has correlated the presence of a TLR8 single nucleotide polymorphism (SNP) (rs3764880:A>G p.Met1Val) with the development of active tuberculosis, suggesting a role for TLR8 in the detection of phagosomal bacteria. Here we provide the first direct evidence that TLR8 sensing is activated in human monocytic cells following Helicobacter pylori phagocytosis. In addition, we show that rs3764880 fine tunes translation of the two TLR8 main isoforms, without affecting protein function. Although we show that TLR8 variant 2 (TLR8v2) is the prevalent form of TLR8 contributing to TLR8 function, we also uncover a role for the TLR8 long isoform (TLR8v1) in the positive regulation of TLR8 function in CD16(+)CD14(+) differentiated monocytes. Thus, TLR8 sensing can be activated following bacterial phagocytosis, and rs3764880 may play a role in the modulation of TLR8-dependent microbicidal response of infected macrophages.
Publisher: Oxford University Press (OUP)
Date: 11-2003
DOI: 10.1189/JLB.0503208
Abstract: Dendritic cells play a major role in HIV pathogenesis. Epithelial dendritic cells appear to be one of the first cells infected after sexual transmission and transfer of the virus to CD4 lymphocytes, simultaneously activating these cells to produce high levels of HIV replication. Such transfer may occur locally in inflamed mucosa or after dendritic cells have matured and migrated to local lymph nodes. Therefore, the mechanism of binding, internalization, infection and transfer of HIV to CD4 lymphocytes is of great interest. Recently, the role of the C-type lectin DC-SIGN as a dendritic cell receptor for HIV has been intensively studied with in vitro monocyte-derived dendritic cells. However, it is clear that other C-type lectin receptors such as Langerin on Langerhan cells and mannose receptor on dermal dendritic cells are at least equally important for gp120 binding on epithelial dendritic cells. C-type lectin receptors play a role in virus transfer to T cells, either via de novo infection (“cis transfer”) or without infection (“in trans” or transinfection). Both these processes are important in vitro, and both may have a role in vivo, although the low-level infection of immature dendritic cells may be more important as it leads to R5 HIV strain selection and persistence of virus within dendritic cells for at least 24 h, sufficient for these cells to transit to lymph nodes. The exact details of these processes are currently the subject of intense study.
Publisher: Rockefeller University Press
Date: 04-1996
Abstract: Dendritic cells isolated from thymus and tonsil were tested for susceptibility to HIV-1 strains that are tropic for macrophages or for T cell lines. DCs were purified by cell sorting and before infection expressed high levels of CD4 and HLA-DR and lacked markers for T, B, NK cells, or macrophages. Viral entry and reverse transcription was found after pulsing with strains of HIV-1 that could infect macrophages. During the first 36 h the PCR signals for gag sequences increased in DCs and macrophages. In contrast little if any viral DNA was found after pulsing macrophages or DCs with HIV-1 that was able to infect T cell lines. DCs pulsed with HIV-1 were able to transmit infection to responding T cells during an allogeneic or superantigen response. Selection for virus able to infect lymphoid DCs and other DCs expressing CD4 and its transfer to T cells during subsequent immune responses may provide a mechanism for the observed predominance of macrophage-tropic HIV-1 after in vivo transmission.
Publisher: Public Library of Science (PLoS)
Date: 09-12-2016
Publisher: Elsevier BV
Date: 12-1990
DOI: 10.1016/0198-8859(90)90042-N
Abstract: Several alleles at multiple HLA loci have been found to be associated with infection with human immunodeficiency virus (HIV): HLA A1 B8, B35 Cw7, Cw4 DR1, DR3 and DQ1, are associated with particular disease manifestations and/or disease progression. Furthermore, in a pilot study we have shown an increase in the frequency of C4 null alleles and suggested that all the reported HLA alleles could reflect association with a limited number of ancestral haplotypes (AHs). On this occasion, we studied 122 Caucasoid patients classified according to Centers for Disease Control (CDC) criteria. The control group consisted of 67 seronegative homosexual or bisexual males at risk of developing HIV infection. C4 null alleles were unequivocally present in 58% of patients in CDC IV compared with 33% of the seronegative subjects (chi 2 = 5.65, p less than 0.05). Furthermore, C4 null alleles could be excluded in only 8% and 16% of CDC III and IV, respectively, but in 30% of the seronegative subjects. An increased frequency of three AHs largely accounted for the increases in C4 null and HLA alleles. To examine the role of specific AHs we undertook a longitudinal analysis of a subgroup of 26 patients who seroconverted under observation. Seventeen of these patients were followed for 32 to 63 months. All seven patients with the 8.1 AH (A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) developed low CD4 lymphocyte counts (less than 450 x 10(6)/l) compared with only 2 of 10 patients without this haplotype (p less than 0.002). All three deaths occurred in patients with the 8.1 AH. The acquired immunodeficiency syndrome developed in three further cases with either 8.1- or B35-bearing (35.x) haplotypes. Sequential CD4/8 ratios showed an early and progressive decline in in iduals with 8.1 or 35.x. Since the 8.1 and 35.x AHs contain deletions of the central major histocompatibility complex (MHC) genes, we suggest that the genes affecting HIV infection and progression are within the central MHC region.
Publisher: The American Association of Immunologists
Date: 09-2018
Abstract: HIV latency occurs predominantly in long-lived resting CD4+ T cells however, latent infection also occurs in T cell subsets, including proliferating CD4+ T cells. We compared the establishment and maintenance of latent infection in nonproliferating and proliferating human CD4+ T cells cocultured with syngeneic myeloid dendritic cells (mDC). Resting CD4+ T cells were labeled with the proliferation dye eFluor 670 and cultured alone or with mDC, plasmacytoid dendritic cells, or monocytes in the presence of staphylococcal enterotoxin B (SEB). Cells were cultured for 24 h and infected with CCR5-tropic enhanced GFP (EGFP) reporter HIV. Five days postinfection, nonproductively infected EGFP− CD4+ T cells that were either nonproliferating (eFluor 670hi) or proliferating (eFluor 670lo) were sorted and cultured for an additional 7 d (day 12) with IL-7 and antiretrovirals. At day 5 postinfection, sorted, nonproductively infected T cells were stimulated with anti–CD3/CD28, and induced expression of EGFP was measured to determine the frequency of latent infection. Integrated HIV in these cells was confirmed using quantitative PCR. By these criteria, latent infection was detected at day 5 and 12 in proliferating T cells cocultured with mDC and monocytes but not plasmacytoid dendritic cells, where CD4+ T cells at day 12 were poor. At day 5 postinfection, nonproliferating T cells expressing SEB-specific TCR Vβ-17 were enriched in latent infection compared with non–SEB-specific TCR Vβ-8.1. Together, these data show that both nonproliferating and proliferating CD4+ T cells can harbor latent infection during SEB-stimulated T cell proliferation and that the establishment of HIV latency in nonproliferating T cells is linked to expression of specific TCR that respond to SEB.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2008
Publisher: Wiley
Date: 12-1990
DOI: 10.1111/J.1744-313X.1990.TB00889.X
Abstract: Insulin-dependent diabetes mellitus (IDDM) is associated with several DR3- or DR4-containing ancestral haplotypes (AHs). Using pulsed field gel electrophoresis (PFGE), long range maps of 35 haplotypes have been derived and classified. Two diabetogenic DR3-containing AHs (8.1 and 18.2) possess deletions in the central non-HLA region these have not been found on non-diabetogenic AHs tested to date. In addition, 8.1 and 18.2 also carry other deletions not found on other AHs. Three DR4 containing AH lack a Not I site, which may imply excision of an unidentified gene. These and other data suggest that deletions may be relevant to the pathogenesis of autoimmune disease, possibly through causing quantitative differences in autoimmune responses involved in IDDM. The MHC contains several regions of potential interest in relation to susceptibility to IDDM these may explain the association with only certain DR3- and DR4-carrying AH and DR3,4 heterozygosity in terms of cis and trans interactions. On the other hand, the class II region may be particularly important in protection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-09-2016
Publisher: Springer Science and Business Media LLC
Date: 03-07-2015
DOI: 10.1007/S00270-015-1162-8
Abstract: To compare the impact of proximal or distal splenic artery embolisation versus that of splenectomy on splenic immune function as measured by IgM memory B cell levels. Patients with splenic trauma who were treated by splenic artery embolisation (SAE) were enrolled. After 6 months splenic volume was assessed by CT, and IgM memory B cells in peripheral blood were measured and compared to a local normal reference population and to a post-splenectomy population. Of the 71 patients who underwent embolisation, 38 underwent proximal embolisation, 11 underwent distal embolisation, 22 patients were excluded, 1 had both proximal and distal embolisation, 5 did not survive and 16 did not return for evaluation. There was a significant difference between splenectomy and proximal or distal embolisation and a trend towards greater preservation of IgM memory B cell number in those with distal embolisation-a difference that could not be attributed to differences in age, grade of injury or residual splenic volume. IgM memory B cell levels are significantly higher in those treated with SAE compared to splenectomy. Our data provide evidence that splenic embolisation should reduce immunological complications of spleen trauma and suggest that distal embolisation may maintain better function.
Publisher: Elsevier BV
Date: 08-1994
DOI: 10.1016/0092-8674(94)90418-9
Abstract: Experimentally, a productive infection with HIV-1 requires that virus be administered to T cells that are activated by mitogens. We describe a productive milieu for HIV-1 within the confines of normal skin that does not require standard stimuli. The milieu consists of dendritic cells and T cells that emigrate from skin and produce distinctive stable, nonproliferating conjugates. These conjugates, upon exposure to each of seven different HIV-1 isolates, begin to release high levels of virus progeny within 4 days. Numerous infected syncytia, comprised of both dendritic and T cells, rapidly develop. We propose that conjugates of dendritic cells and T cells, as found in the external linings of organs involved in sexual transmission of HIV-1, represent an important site for the productive phase of HIV-1 infection. Because the affected T cells carry the memory phenotype, this site additionally provides a mechanism for the chronic depletion of CD4+ memory cells in HIV-1 disease.
Publisher: The American Association of Immunologists
Date: 2022
Abstract: In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.
Publisher: Frontiers Media SA
Date: 09-11-2017
Publisher: Wiley
Date: 27-06-2002
DOI: 10.1002/CYTO.10118
Abstract: Heterogeneity within human dendritic cells (DCs) has been described but its functional relationships to cells of macrophage lineage and its role in human immunodeficiency virus (HIV) infection in vivo remain unclear. Tonsil macrophages and DCs were isolated from low-density cells by negative selection and DCs were sorted into myeloid and plasmacytoid populations using antibodies to CD11c or CD123. Phagocytosis of latex beads and uptake of dye-labeled target cells were compared by flow cytometry and CD68 and S-100 by immunofluorescence on cytospins of sorted cells. Bead uptake and membrane dye transfer were found in both blood and tonsil CD11c(+) DCs and in CD14(+) cells particularly from blood monocytes. CD11c(-) DCs were poorly phagocytic but took up fluorescent dye from intact, necrotic or apoptotic cells. Tonsil DCs and macrophages expressed both CD68 and S-100 but CD11c(-) DCs expressed CD68 only. Freshly isolated CD11c(+) tonsil DCs are similar to CD14(+) macrophages in phagocytic function but the poorly phagocytic CD11c(-) DCs can also take up membrane from target cells. The intracellular markers commonly used to identify DCs and macrophages in situ do not identify accurately the CD11c(-) DC subset nor do they distinguish tonsil macrophages from DCs.
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S1386-6532(01)00194-9
Abstract: Dendritic cells (DC) are believed to be one of the first cell types infected during HIV transmission. Recently a single C-type lectin receptor (CLR), DC-SIGN, has been reported to be the predominant receptor on monocyte derived DC (MDDC) rather than CD4. The role of other CLRs in HIV binding and HIV binding by CLRs on other types of DC in vivo is largely unknown. Review HIV binding to DC populations, both in vitro and in vivo, in light of the immense interest of a recently re-identified CLR called DC-SIGN. From recent work, it is clear that immature MDDC have a complex pattern of HIV gp120 binding. In contrast to other cell types gp120 has the potential to bind to several receptors on DC including CD4 and several types of C type lectin receptor, not just exclusively DC-SIGN. Given the erse types of DC in vivo future work will need to focus on defining the receptors for HIV binding to these different cell types. Mucosal transmission of HIV in vivo targets immature sessile DCs, including Langerhans cells which lack DC-SIGN. The role of CLRs and DC-SIGN in such transmission remains to be defined.
Publisher: Elsevier BV
Date: 08-2001
Publisher: Springer Science and Business Media LLC
Date: 22-09-2011
DOI: 10.1038/GENE.2011.65
Abstract: We previously found an association between faster CD4+ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-α (IL-7Rα) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n=352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Rα single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n=57). Soluble (s)IL-7Rα levels were measured by ELISA. In UARTO, IL-7Rα haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P=0.020) and no association was found with LMM (P=0.958). The tagging-SNP for IL-7Rα haplotype-2 (rs6897932) was associated with decreased sIL-7Rα (P<0.001). The haplotypes for the IL-7Rα were significantly different in Africans and Caucasians. Using IL-7Rα genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P=0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P=0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Rα haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Rα SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.BBMT.2017.07.025
Abstract: Opportunistic infections such as cytomegalovirus (CMV) reactivation and invasive fungal disease (IFD) cause significant morbidity and mortality to recipients of hematopoietic stem cell transplant (HSCT). We aimed to characterize the risk and relationship of CMV reactivation post-HSCT to IFD in the current era of CMV viral load monitoring using highly sensitive plasma DNA. A multicenter, retrospective, cohort study was conducted of consecutive patients undergoing allogeneic HSCT from January 2006 to December 2010 in Melbourne, Australia. CMV reactivation was defined as detection of plasma CMV DNA ≥ 546 IU/mL or development of CMV disease. IFD was classified in accordance with current international consensus guidelines. Of the 419 study participants, the median age was 44 years (IQR, 34 to 54), and CMV reactivation occurred in 106 participants (25%) at a median time of 56 days (IQR, 45 to 79). Thirty-eight participants (9.1%) were identified with 41 cases of IFD (n = 22 proven, n = 8 probable, n = 11 possible) at a median time of 76 days (IQR, 24 to 344). The incidence of IFD was higher in participants with CMV reactivation compared with no CMV reactivation (15% versus 7%, P = .012). In a multivariate analysis CMV reactivation remained an independent risk factor for IFD (hazard ratio, 3.7 95% CI, 1.6 to 8.5 P = .002). The cumulative incidence of all IFD in patients with and without CMV reactivation using a competing risk regression was a hazard ratio of 2.2 (95% CI, 1.2 to 4.1 P = .017) and for late-onset IFD was a hazard ratio of 3.95 (95% CI, 1.7 to 9 P = .001). The median time to IFD onset was longer in participants with than without CMV reactivation (184 versus 37 days, P = .03). The peak viral load, detection of any level of viremia, and experiencing more than 1 episode of CMV reactivation were not associated with development of IFD. CMV reactivation in HSCT recipients in the post-transplant period is associated with an increased risk of developing late-onset IFD. Further research is warranted to understand the interaction between these 2 important infectious complications.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2018
Publisher: Wiley
Date: 10-1999
DOI: 10.1046/J.1440-1711.1999.00853.X
Abstract: Dendritic cells (DC) have been implicated in the initial selection for macrophage-tropic HIV-1 during transmission and in the generation of high-level virus replication during interactions with CD4 T cells. The role of DC as viral reservoirs and the extent of productive infection is unclear, but the ability to generate large numbers of DC from blood monocytes has produced a tractable model for study of DC-HIV-1 interactions. When cultured in granulocyte-macrophage colony stimulating factor and IL-4, sorted CD14+ monocytes rapidly lost phagocytic function for both 93 nm and 977 nm latex particles and developed the surface markers and function of DC. After 7 days, when returned to medium containing human serum without cytokines, some monocyte-derived dendritic cells (MDDC) became adherent, but retained the costimulatory markers CD80 and CD86 and continued to express CD83 and CD40. The MDDC stimulated allogeneic CD4 T cells, did not express new macrophage markers and remained non-phagocytic. With or without TNF-alpha, MDDC generated in cytokines were infected by macrophage and T cell-tropic virus and produced higher reverse transcriptase levels than did the autologous monocyte-derived macrophages (MDM). When added to T cells, the infected MDDC were able to infect T cells with a wider range of viral isolates than were MDM.
Publisher: Mary Ann Liebert Inc
Date: 1994
Abstract: Interacting dendritic cells and helper CD4+ lymphocytes form a microenvironment that is permissive for HIV-1 replication. The virus need only be pulsed initially onto the dendritic cells, which then transfer HIV-1 to the lymphocytes that are responding to presented antigens or superantigens. We have pursued underlying mechanisms in this system, because it provides a model for the infection of antigen-reactive, primary T cells. Pulsing the T cells with HIV-1 results in much less of a subsequent infection than does pulsing the dendritic cells. The latter pulse occurs effectively in the presence of AZT. Direct examination of the interacting dendritic cells and T cells reveals extensive production of p24 by many of the lymphocytes, including syncytia. The majority of the responding T cells die during the coculture. Apoptosis accounts for much of this death as revealed by in situ nick translation assays for DNA endonucleolysis, and hypodiploid profiles on staining with DNA-binding dyes. Therefore the microenvironment that is generated between antigen-presenting dendritic cells and T cells reveals the cytopathic potential of HIV-1, because there is such extensive and rapid death by apoptosis of antigen-reactive T cells.
Publisher: Oxford University Press (OUP)
Date: 18-04-2017
Abstract: A simple test to identify recovery of CMV-specific T-cell immunity following hematopoietic stem cell transplantation (HSCT) could assist clinicians in managing CMV-related complications. In an observational, multicenter, prospective study of 94 HSCT recipients we evaluated CMV-specific T-cell immunity at baseline, 3, 6, 9, and 12 months after transplant using the Quantiferon-CMV, an enzyme-linked immunosorbent spot assay (ELISpot), and intracellular cytokine staining. At 3 months after HSCT, participants who developed CMV disease (n = 8) compared with CMV reactivation (n = 26) or spontaneous viral control (n = 25) had significantly lower CD8+ T-cell production of interferon-γ (IFN-γ) in response to CMV antigens measured by Quantiferon-CMV (P = .0008). An indeterminate Quantiferon-CMV result had a positive predictive value of 83% and a negative predictive value of 98% for identifying participants at risk of further CMV reactivation. Participants experiencing CMV reactivation compared with patients without CMV reactivation had a reduced proportion of polyfunctional (IFN-γ+/tumor necrosis factor α-positive) CD4+ and CD8+ T cells and a higher proportion of interleukin 2-secreting cells (P = .01 and P = .002, respectively). Quantifying CMV-specific T-cell immunity after HSCT can identify participants at increased risk of clinically relevant CMV-related outcomes.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2013
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-07-1992
Abstract: The paucity of virus-laden CD4+ cells in in iduals infected with human immunodeficiency virus type-1 (HIV-1) contrasts with the greatly reduced numbers and function of these lymphocytes. A pathway is described whereby dendritic cells carry HIV-1 to uninfected T cells, lifying the cytopathic effects of small amounts of virus. After exposure to HIV-1, dendritic cells continue to present superantigens and antigens, forming clusters with T cells that are driven to replicate. Infection of the dendritic cells cannot be detected, but the clustered T cells form syncytia, release virions, and die. Carriage of HIV-1 by dendritic cells may facilitate the lysis and loss of antigen specific CD4+ T cells in acquired immunodeficiency syndrome.
Publisher: Public Library of Science (PLoS)
Date: 06-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2017
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.CLIM.2007.08.016
Abstract: Thymic dendritic cells (DCs) are a unique subset of bone marrow-derived professional antigen presenting cells (APCs) that interact closely with developing thymocytes and play a crucial role in the process of negative selection and subsequent deletion of potential auto-reactive T cell clones. HIV-1 infection of the thymus has been implicated in the defective regeneration of the CD4(+) T cell pool in infected in iduals. Thymic DCs are permissive to infection by HIV-1 and given their important role in T cell development, infected DCs within the thymus may contribute to the depletion of T cells. Here we review the phenotype and function of different DC subsets found within the human thymus and discuss potential mechanisms of how DCs may be important in CD4(+) T cell dysfunction in HIV-1 infection.
Publisher: Frontiers Media SA
Date: 14-05-2018
Publisher: Elsevier BV
Date: 07-2013
Publisher: Springer Science and Business Media LLC
Date: 26-07-2016
Publisher: Springer Science and Business Media LLC
Date: 11-09-2015
Publisher: Public Library of Science (PLoS)
Date: 02-06-2011
Publisher: Oxford University Press (OUP)
Date: 02-1993
Abstract: Interleukin-2 (IL-2) is a key cytokine in cellular immunity. Human immunodeficiency virus type 1 (HIV-1)-infected in iduals lack IL-2 because of low CD4+ T lymphocyte numbers. In an attempt to enhance cellular immunity, low-dose recombinant human (rh) IL-2 at 10 micrograms or 180,000 units or its polyethylene glycol (PEG) derivative at 9 micrograms or 36,000 units was given by intracutaneous injection to 8 HIV-1-infected men for 30 days. Participants had no evidence of opportunistic infection and received concurrent zidovudine. IL-2 treatment was nontoxic and elicited a local cellular response resembling classic delayed-type hypersensitivity (DTH) with local interferon-gamma production, even in anergic patients. Systemic responses included enhanced DTH responses to recall antigens, improved in vitro proliferative responses to mitogen, and enhanced NK cell activity. Peripheral leukocyte phenotype and virus titers were unchanged. Long-term studies of low-dose IL-2 are warranted to determine whether immunoenhancing effects can be sustained and if they are associated with improved clinical course.
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.CLIM.2011.09.002
Abstract: Functional naïve T-cells are critical for an effective immune response to multiple pathogens. HIV leads to a significant reduction in CD4+ naïve T-cell number and impaired function and there is incomplete recovery following combination antiretroviral therapy (cART). Here we review the basic homeostatic mechanisms that maintain naïve CD4+ T-cells and discuss recent developments in understanding the impact of HIV infection on naïve CD4+ T-cells. Finally we review therapeutic interventions in HIV-infected in iduals aimed at specifically enhancing recovery of naïve CD4+ T-cells.
Publisher: Elsevier BV
Date: 05-1991
DOI: 10.1016/0198-8859(91)90046-C
Abstract: In humans, certain major histocompatibility complex (MHC) supratypes mark unique DNA segments which have been conserved from a common but remote ancestor. In order to determine whether these ancestral haplotypes (AHs) exist in nonhuman primates, C4 allotyping was undertaken on 71 chimpanzees. Four large pedigrees were available. There are at least seven codominant C4 alleles at two loci. Null alleles are also present. It was possible to assign class I, class II, and C4 alleles to 37 unrelated haplotypes several supratypes occurred two or more times. These putative AHs included some with alleles which resemble those carried by certain human AHs. These data provide evidence that similar MHC AHs are present in the chimpanzee and human. The present approach provides a basis for comparative studies examining the evolutionary and functional significance of the MHC.
Publisher: Rockefeller University Press
Date: 18-05-1998
Abstract: Macrophage tropic HIV-1 is predominant during the initial viremia after person to person transmission of HIV-1 (Zhu, T., H. Mo, N. Wang, D.S. Nam, Y. Cao, R.A. Koup, and D.D. Ho. 1993. Science. 261:1179–1181.), and this selection may occur during virus entry and carriage to the lymphoid tissue. Human skin explants were used to model HIV-1 selection that may occur at the skin or mucosal surface. Macrophage tropic, but not T cell line tropic strains of HIV-1 applied to the abraded epidermis were recovered from the cells emigrating from the skin explants. Dermis and epidermis were separated by dispase digestion after virus exposure to determine the site of viral selection within the skin. Uptake and transmission to T cells of all HIV-1 isolates was found with the dermal emigrant cells, but only macrophage tropic virus was transferred by emigrants from the epidermis exposed to HIV-1, indicating selection only within the epidermis. CD3+, CD4+ T cells were found in both the dermal and epidermal emigrant cells. After cell sorting to exclude contaminating T cells, macrophage tropic HIV-1 was found in both the dermal emigrant dendritic cells and in dendritic cells sorted from the epidermal emigrants. These observations suggest that selective infection of the immature epidermal dendritic cells represents the cellular mechanism that limits the initial viremia to HIV-1 that can use the CCR5 coreceptor.
Publisher: Oxford University Press (OUP)
Date: 15-06-2003
DOI: 10.1086/375351
Abstract: T cell dynamics and viral genotype were studied in human immunodeficiency virus 1-infected in iduals receiving antiretroviral therapy who were viremic and had either increasing (discordant immunological responders) or decreasing (nonresponders) CD4(+) T cell counts. A comparison was made with treated in iduals who were not viremic and had increasing CD4(+) T cell counts (complete responders). Nonresponders had higher CD4(+) T cell proliferation (as assessed by Ki67 expression) and immune activation (as assessed by CD38 and human leukocyte antigen-DR expression), together with a reduction in T cell receptor excision circles, compared with discordant immunological responders and complete responders, which suggests that there is enhanced viral pathogenicity in both peripheral T cells and the thymus. Although there was a high prevalence of mutations in the protease and reverse transcriptase genes in discordant immunological responders, these changes were also observed in nonresponders.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2017
Publisher: The American Association of Immunologists
Date: 15-10-2002
DOI: 10.4049/JIMMUNOL.169.8.4657
Abstract: We quantified T cell proliferation and thymic function in primary HIV infection (PHI n = 19) and chronic HIV infection (CHI n = 14) by measuring Ki67 staining and TCR excision circle (TREC) number. After antiretroviral therapy of PHI there is a profound decrease in the number and percentage of Ki67+ T cells (& % Ki67+) with no significant increase in TREC per million cells and a transient increase in TREC per milliliter. In contrast, after antiretroviral therapy of CHI there is a reduction in the percentage but little change in the total number of Ki67+CD4+ T cells associated with increases in both TREC per million cells and TREC per milliliter. Using a mathematical model that accounts for proliferation, death, and redistribution of T cells, we find that redistribution is consistent with the TREC changes observed during treatment of PHI and that an increase in thymic output is needed to explain the increase in TREC during treatment of CHI. Consideration of TREC per milliliter shows that changes in proliferation alone cannot explain the changes in TREC. In addition, although increased proliferation of memory cells in HIV infection has been established, we find no difference in TREC per million CD45RA− “memory” T cells between healthy and infected in iduals (p = 0.154 for CD4+ p = 0.383 for CD8+). Finally, although the number of TREC per million cells is always much lower in memory T cells than in naive T cells, in the setting of HIV infection, given that memory cells make up a larger proportion of total T cells, we find that 50% of TREC per milliliter in CD4+ T cells is harbored in the CD45RA− “memory” subset of our infected subjects.
Publisher: Wiley
Date: 05-2010
Publisher: Oxford University Press (OUP)
Date: 19-12-2006
DOI: 10.1189/JLB.0705377
Abstract: A central feature of the inflammatory pathology in Alzheimer’s disease is activated microglia clustered around aggregated amyloid β (Aβ) peptide-containing plaques. In vitro-cultured microglia can be activated to an inflammatory state by aggregated Aβ with the induction of a range of different neurotoxic factors and provide a model system for studying microglia Aβ interactions. Gene expression responses of human postmortem brain-derived microglia to aggregated Aβ were measured using whole genome microarrays to address the hypothesis that Aβ interactions with human microglia primarily induce proinflammatory genes and not activation of genes involved in Aβ phagocytosis and removal. The results demonstrated that Aβ activation of microglia induced a large alteration in gene transcription including activation of many proinflammatory cytokines and chemokines, most notably, interleukin (IL)-1β, IL-8, and matrix metalloproteinases (MMP), including MMP1, MMP3, MMP9, MMP10, and MMP12. All of these genes could lify ongoing inflammation, resulting in further neuronal loss. Changes in expression of receptors associated with Aβ phagocytosis did not match the changes in proinflammatory gene expression. Time-course gene expression profiling, along with real-time polymerase chain reaction validation of expression changes, demonstrated an acute phase of gene induction for many proinflammatory genes but also chronic activation for many other potentially toxic products. These chronically activated genes included indoleamine 2,3-dioxygenase and kynureninase, which are involved in formation of the neurotoxin quinolinic acid, and S100A8, a potential proinflammatory chemokine. These studies show that activation of microglia by Aβ induces multiple genes that could be involved in inflammatory responses contributing to neurodegenerative processes.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2015
Publisher: The American Association of Immunologists
Date: 03-2020
Abstract: In people living with HIV on antiretroviral therapy, HIV latency is the major barrier to a cure. HIV persists preferentially in CD4+ T cells expressing multiple immune checkpoint (IC) molecules, including programmed death (PD)-1, T cell Ig and mucin domain-containing protein 3 (TIM-3), lymphocyte associated gene 3 (LAG-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). We aimed to determine whether these and other IC molecules have a functional role in maintaining HIV latency and whether blocking IC molecules with Abs reverses HIV latency. Using an in vitro model that establishes latency in both nonproliferating and proliferating human CD4+ T cells, we show that proliferating cells express multiple IC molecules at high levels. Latent infection was enriched in proliferating cells expressing PD-1. In contrast, nonproliferating cells expressed IC molecules at significantly lower levels, but latent infection was enriched in cells expressing PD-1, TIM-3, CTL-associated protein 4 (CTLA-4), or B and T lymphocyte attenuator (BTLA). In the presence of an additional T cell–activating stimulus, staphylococcal enterotoxin B, Abs to CTLA-4 and PD-1 reversed HIV latency in proliferating and nonproliferating CD4+ T cells, respectively. In the absence of staphylococcal enterotoxin B, only the combination of Abs to PD-1, CTLA-4, TIM-3, and TIGIT reversed latency. The potency of latency reversal was significantly higher following combination IC blockade compared with other latency-reversing agents, including vorinostat and bryostatin. Combination IC blockade should be further explored as a strategy to reverse HIV latency.
Publisher: American Society of Hematology
Date: 15-12-2007
DOI: 10.1182/BLOOD-2007-06-097907
Abstract: Latent HIV-1 infection of resting memory CD4+ T cells represents the major barrier to HIV-1 eradication. To determine whether the CCR7 ligands involved in lymphocyte migration can alter HIV-1 infection of resting CD4+ T cells, we infected purified resting CD4+ T cells after incubation with the chemokines CCL19 and CCL21. Incubation with CCL19 or CCL21 did not alter markers of T-cell activation or proliferation. However, after HIV-1 infection of CCL19- or CCL21-treated CD4+ T-cells, we observed low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts. Restimulation of CCL19-treated infected CD4+ T cells resulted in virus production consistent with establishment of postintegration latency. CCR7 ligands facilitate efficient entry of HIV-1 into resting CD4+ T cells. These studies demonstrate a unique action of the chemokines CCL19 and CCL21 and provide a novel model with which to study HIV-1 latency in vitro.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-06-2016
Publisher: Springer Science and Business Media LLC
Date: 12-10-2011
Abstract: We recently described that HIV latent infection can be established in vitro following incubation of resting CD4+ T-cells with chemokines that bind to CCR7. The main aim of this study was to fully define the post-integration blocks to virus replication in this model of CCL19-induced HIV latency. High levels of integrated HIV DNA but low production of reverse transcriptase (RT) was found in CCL19-treated CD4+ T-cells infected with either wild type (WT) NL4.3 or single round envelope deleted NL4.3 pseudotyped virus (NL4.3- Δenv). Supernatants from CCL19-treated cells infected with either WT NL4.3 or NL4.3- Δenv did not induce luciferase expression in TZM-bl cells, and there was no expression of intracellular p24. Following infection of CCL19-treated CD4+ T-cells with NL4.3 with enhanced green fluorescent protein (EGFP) inserted into the nef open reading frame (NL4.3- Δnef-EGFP), there was no EGFP expression detected. These data are consistent with non-productive latent infection of CCL19-treated infected CD4+ T-cells. Treatment of cells with phytohemagluttinin (PHA)/IL-2 or CCL19, prior to infection with WT NL4.3, resulted in a mean fold change in unspliced (US) RNA at day 4 compared to day 0 of 21.2 and 1.1 respectively (p = 0.01 n = 5), and the mean expression of multiply spliced (MS) RNA was 56,000, and 5,000 copies/million cells respectively (p = 0.01 n = 5). In CCL19-treated infected CD4+ T-cells, MS-RNA was detected in the nucleus and not in the cytoplasm in contrast to PHA/IL-2 activated infected cells where MS RNA was detected in both. Virus could be recovered from CCL19-treated infected CD4+ T-cells following mitogen stimulation (with PHA and phorbyl myristate acetate (PMA)) as well as TNFα, IL-7, prostratin and vorinostat. In this model of CCL19-induced HIV latency, we demonstrate HIV integration without spontaneous production of infectious virus, detection of MS RNA in the nucleus only, and the induction of virus production with multiple activating stimuli. These data are consistent with ex vivo findings from latently infected CD4+ T-cells from patients on combination antiretroviral therapy, and therefore provide further support of this model as an excellent in vitro model of HIV latency.
Publisher: Springer Science and Business Media LLC
Date: 1993
DOI: 10.1007/BF00187457
Publisher: Mary Ann Liebert Inc
Date: 03-2014
Publisher: Public Library of Science (PLoS)
Date: 04-08-2011
Publisher: Oxford University Press (OUP)
Date: 12-2010
DOI: 10.1086/656721
Abstract: Naive T cell recovery is critical for successful immune reconstitution after antiretroviral therapy (ART), but the relative contribution of CD31(+) and CD31⁻ naive T cells to immune reconstitution and viral persistence is unknown. In a cross-sectional (n = 94) and longitudinal (n = 10) study of human immunodeficiency virus (HIV)-infected patients before and after ART, we examined the ratio of CD31(+) to CD31⁻ naive CD4(+) T cells. In the longitudinal cohort we then quantified the concentration of HIV-1 DNA in each cell subset and performed single-genome lification of virus from memory and naive T cells. Patients receiving ART had a higher proportion of CD31(+) CD4(+) T cells than HIV-1-infected in iduals naive to ART and uninfected control subjects (P < .001 and .007, respectively). After 24 months of ART, the proportion of CD31(+) naive CD4(+) T cells did not change, the concentration of HIV-1 DNA in memory CD4(+) T cells significantly decreased over time (P < .001), and there was no change in the concentration of HIV-1 DNA in CD31(+) or CD31⁻ naive CD4(+) T cells (P = .751 and .251, respectively). Single-genome lification showed no evidence of virus compartmentalization in memory and naive T cell subsets before or after ART. After ART, both CD31(+) and CD31⁻ naive CD4(+) T cells expand, and both subsets represent a stable, persistent reservoir of HIV-1.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Rockefeller University Press
Date: 06-1990
Abstract: We have examined the hypothesis that MHC ancestral haplotypes have a specific content of genes regulating the extent of autoimmune reactions. Gene copy number was quantitated by objective densitometry after PFGE was used to separate heterozygous AHs of different lengths. Initially we analyzed ex les of known gene copy number at the C4 and 21 hydroxylase loci and showed that the approach provides predictable results. We then studied heterozygotes containing one characterized and one uncharacterized AH with particular attention to the gene copy number at the C4, Cyp21, and DRB loci. Each AH studied has a characteristic gene copy number at each locus studied. The same may be true of TNF, but other possibilities must be considered. AHs are markers for extensive chromosomal segments including particular numbers of several functional genes. Since AHs mark susceptibility to autoimmune disease, differences in gene copy number may be implicated.
Publisher: Wiley
Date: 02-2003
DOI: 10.1046/J.1440-1711.2003.01133.X
Abstract: The ability of antigens to elicit immune responses depends upon their initial recognition, uptake, processing and presentation by dendritic cells. This fact has been recognized by many workers and dendritic cells are now regarded as natural 'adjuvants' in the business of vaccine design. One way of persuading dendritic cells to become interested in foreign material is to decorate it with lipid moieties found in bacteria. This approach has been used in the context of synthetic peptide-based immunogens and depending on the nature of the epitopes included, can provide highly immunogenic structures capable of eliciting antibody or cytotoxic T cell responses. In this paper we describe the results of experiments in which the stimulatory effects of peptide-based vaccine candidates on human dendritic cells are examined. Our findings indicate that lipidated structures comprising vaccine target sequences of viral origin coupled to the synthetic lipid groups of bacteria are able to induce the maturation of dendritic cells, as measured by the expression of cell surface MHC class II molecules.
Publisher: Springer Science and Business Media LLC
Date: 03-1977
DOI: 10.1007/BF00218700
Publisher: American Society for Microbiology
Date: 03-2005
DOI: 10.1128/IAI.73.3.1714-1722.2005
Abstract: Gene expression in murine dendritic cells (DCs) infected with green fluorescent protein-expressing Salmonella enterica serovar Typhimurium BRD509 was studied by mRNA differential display. Infected DCs were sorted from uninfected cells by flow cytometry. The mRNA expression patterns of infected and uninfected cells revealed a number of differentially expressed transcripts, which included the macrophage-derived chemokine (MDC). Up-regulation of MDC transcription in infected DCs was confirmed by Northern blotting, and the kinetics of MDC expression was examined by real-time reverse transcription-PCR, with which 31- and 150-fold increases were detected at 2 and 6 h postinfection, respectively. The increased release by DCs of MDC into culture media was detected by an enzyme-linked immunosorbent assay. The biological activity of MDC was investigated in in vitro and in vivo assays. In vitro, supernatants from S. enterica serovar Typhimurium-infected DCs were chemoattractive to T cells, and neutralization of MDC in these supernatants inhibited T-cell migration. Passive transfer of anti-MDC antibody to mice infected with BRD509 revealed that neither growth of the bacterium nor resistance of the mice to reinfection was affected and that in vivo inhibition of MDC did not affect T-cell responses, as measured by the gamma interferon ELISPOT method 3 days after challenge infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2009
Publisher: Wiley
Date: 06-2003
Abstract: We have used a TCR beta-chain transgenic mouse to examine the relationship between the ability of a T cell to bind soluble class I-peptide complexes and its response to antigenic stimulation in vivo. T cells from gBT-I.3beta TCR beta-chain transgenic mice preferentially carried TCR alpha-chains bearing the same Valpha2 V region as found in the parent receptor specific for an immunodominant HSV-1 gB-peptide. Furthermore, CD8(+) T cells from these mice bound K(b)-gB tetrameric complexes with relatively high frequency, and most of these cells contained a Valpha2 TCR alpha-chain. Detailed sequence analysis of the tetramer-binding peripheral T cells showed that this was a heterogenous population expressing TCR with only partial sequence similarity to the parent receptor, which took the form of preferential inclusion of the parental Jalpha16 element. Infection with HSV-1, however, selected a subset of tetramer-positive T cells. This was based on the emergence of a co-dominant Jalpha usage and selection of a restricted CDR3alpha length. Therefore, the ability to bind soluble MHC-peptide complexes does not always correlate with the ability of a T cell to respond to its cognate antigen after in vivo stimulation.
Publisher: Oxford University Press (OUP)
Date: 09-01-2013
Abstract: Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected in iduals on cART via inhibition of telomerase activity. Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART. Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 μM. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47 P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11 P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01). NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected in iduals on cART.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41598-019-51913-3
Abstract: Interleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses and is potentially useful as a prognostic marker in inflammation. IRAK3 inhibits signalling cascades downstream of myddosome complexes associated with toll like receptors. IRAK3 contains a death domain that interacts with other IRAK family members, a pseudokinase domain and a C-terminus domain involved with tumour necrosis factor receptor associated factor 6 (TRAF6). Previous bioinformatic studies revealed that IRAK3 contained a guanylate cyclase centre in its pseudokinase domain but its role in IRAK3 action is unresolved. We demonstrate that wildtype IRAK3 is capable of producing cGMP. Furthermore, we show that a specific point mutation in the guanylate cyclase centre reduced cGMP production. Cells containing toll like receptor 4 and a nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB) reporter system were transfected with IRAK3 or mutant IRAK3 proteins. Cell-permeable cGMP treatment of untransfected control cells suppresses downstream signalling through modulation of the NFĸB in the presence of lipopolysaccharides. Cells transfected with wildtype IRAK3 also suppress lipopolysaccharide induced NFĸB activity in the absence of exogenous cGMP. Lipopolysaccharide induced NFĸB activity was not suppressed in cells transfected with the IRAK3 mutant with reduced cGMP-generating capacity. Whereas in the presence of exogenously applied cell-permeable cGMP the IRAK3 mutant was able to retain its function by suppressing lipopolysaccharide induced NFĸB activity. Furthermore, increasing the amount of membrane permeable cGMP did not affect IRAK3’s ability to reduce NFĸB activity. These results suggest that cGMP generated by IRAK3 may be involved in regulatory function of the protein where the presence of cGMP may selectively affect downstream signalling pathway(s) by modulating binding and/or activity of nearby proteins that interact in the inflammatory signalling cascade.
Publisher: Oxford University Press (OUP)
Date: 05-1992
DOI: 10.1111/J.1365-2249.1992.TB03066.X
Abstract: We have considered the possibility that antigen-presenting cells of the dendritic cell lineage may be infected in vivo and spread HIV-1 at the time dendritic cells initiate the clonal expansion of antigen-specific T cells. Dendritic cells were isolated from 25 HIV-1–infected subjects (CDC stages II- IV). Fewer dendritic cells were recovered from most infected subjects. Reduced numbers of total non-T cells were also found in these patients, so that preferential loss of dendritic cells did not occur. Dendritic cell function was assessed by stimulatory capacity for allogeneic CD4+ T cells in the mixed leucocyte reaction (MLR). Potent M LR stimulator activity was retained in the dendritic cell-enriched populations from HIV-infected patients. Seven out of nine patients without AIDS (asymptomatic, lymphadenopathy or ARC) and three out of six patients with AIDS had proliferative responses equivalent to those induced by dendritic cells from controls. Dendritic cells from HIV+ subjects were able to initiate the expansion of allogeneic CD4+ T cell clones with cloning efficiency not different from controls and without evidence of cytopathic effect in the expanding CD4+ clones. In situ hybridization of the different mononuclear cell populations with a gag-specific riboprobe demonstrated positive cells in the T cell fractions of 12 of the 15 patients tested. None of the asymptomatic or ARC patients had riboprobe-positive cells in the dendritic cell-enriched populations. Four out of nine patients with AIDS had cells positive for HIV-1 expression in the dendritic cell-enriched fraction. However, the positive cells had the nuclear profile of lymphocytes, and by cytofluorography some residual low-density T cells were present. By limiting dilution and polymerase chain reaction (PCR), CD4+ lymphocytes carried HIV provirus in inocula of 500–5000 cells, while provirus could only be detected in 50000 cells from the dendritic cell-enriched fraction. The latter signal may be due to the demonstrated levels of T cell contamination. Our data indicate that productive or latent HIV-1 infection of blood dendritic cells in vivo is rare, certainly no greater than in T lymphocytes, and that in vitro dendritic cell preparations from patients can expand CD4’ T cells efficiently and therefore may be able to expand T cells with immunotherapeutic activity.
Publisher: Oxford University Press (OUP)
Date: 09-1994
DOI: 10.1002/JLB.56.3.257
Abstract: We review recent work on the extent of HIV-1 infection of dendritic cells (DCs) and the consequences of exposure to virus. The reported levels of infection of DCs from blood have varied from “explosive” to “undetectable.” The only study that used sorted DCs demonstrated little if any infectability, which may not be surprising given the very low levels of CD4 on the populations that were studied. HIV-1-pulsed, highly purified DCs function as potent antigen-presenting cells during the mixed leukocyte reaction and responses to superantigens. At the same time that the HIV-1-pulsed DCs stimulate CD4+ T cells in DC-T clusters, the virus is transferred to the responding lymphocytes and a vigorous productive infection of the T cells takes place. This pool of transferable HIV-1 is short lived in cultured human blood DCs and likely reflects the capacity of these cells to internalize and recycle vesicles in the endocytic pathway, as revealed with experiments using 0.1-μm fluorescent latex beads. Current efforts are directed to analyzing the interaction of HIV-1 with several populations of DCs that express higher levels of CD4. These include DCs studied in fresh, uncultured blood, as well as skin, thymus, and tonsil DCs. In each case, entry and reverse transcription of HIV-1 are seen, but again, coculture with T cells is required for a productive infection to take place. We conclude that DCs could play a critical role in the pathogenesis of HIV-1 infection, but that the interaction with CD4+ T cells is a critical variable in analyzing the extent of productive infection and its consequences. J. Leukoc. Biol. 56: 257–265 1994.
Publisher: Wiley
Date: 11-2009
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1199
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.JVIROMET.2010.01.010
Abstract: Efficient isolation of replication-competent virus from plasma of patients infected with HIV-1 is needed to characterize important clinical parameters of virus. However, addition of plasma to in vitro cultures results in clot formation. Blood from HIV-1 infected patients was collected in the presence of three commonly used anticoagulants (ACD, heparin and EDTA) and plasma was isolated. Plasma was then used to infect HIV-1 indicator cell lines (TZM-bl and GHOST) with spinoculation in the presence or absence of additional heparin and positively charged polymers. The presence of additional heparin during inoculation significantly reduced clot formation without affecting the sensitivity of HIV-1 infection in the GHOST cell line. However, heparin reduced the frequency of HIV-1 infection of the TZM-bl cell line. Using plasma from patients with HIV RNA>1000 copies/ml (n=58), the frequency of HIV-1 isolation was 92% in GHOST (n=51) and 54% in TZM-bl (n=26) cell lines. A sensitive method was developed for rapid isolation of infectious HIV-1 from plasma of patients with HIV RNA>1000 copies/ml that includes spinoculation and the addition of heparin during infection of GHOST cells. This technique could be used for rapid evaluation of viral fitness, co-receptor usage or drug resistance without the need for viral lification.
Publisher: Wiley
Date: 08-2013
DOI: 10.1002/RMV.1753
Abstract: Dendritic cells (DCs) are found at the portals of pathogen entry such as the mucosal surfaces of the respiratory, gastrointestinal and genital tracts where they represent the first line of contact between the immune system and the foreign invaders. They are found throughout the body in multiple subsets where they express unique combinations of C-type lectin receptors to best aid them in detection of pathogens associated with their anatomical location. DCs are important in the establishment in HIV infection for two reasons. Firstly, they are one of the first cells to encounter the virus, and the specific interaction that occurs between these cells and HIV is critical to HIV establishing a foothold infection. Secondly and most importantly, HIV is able to efficiently transfer the virus to its primary target cell, the CD4(+) T lymphocyte, in which it replicates explosively. Infection of CD4(+) T lymphocytes via DCs is far more efficient than direct infection. This review surveys the various DCs subsets found within the human sexual mucosa and their interactions with HIV. Mechanisms of HIV uptake are discussed as well as how the virus then traffics through the DC and is transferred to T cells. Until recently, most research has focussed on vaginal transmission despite the increased transmission rate associated with anal intercourse. Here, we also discuss recent advances in our understanding of HIV transmission in the colon.
Publisher: Elsevier BV
Date: 10-1989
DOI: 10.1016/0198-8859(89)90094-3
Abstract: We describe here an Nco I restriction fragment length polymorphism of tumor necrosis factor carried by the 8.1 (HLA-A1,B8,BfS,C4AQ0,C4B1,DR3) and the 44.1 (HLA-B44,BfS,C4A3,C4BQ0,DR4) ancestral haplotypes associated with complications of rheumatoid arthritis. By examining multiple ex les of these and other ancestral haplotypes it was seen that 8.1 and 44.1 ancestral haplotypes yield fragments of approximately 5.5 kb while many other ancestral haplotypes carry fragments of approximately 10.5 kb. The polymorphism is associated with the ancestral haplotype rather than the HLA-B or -DR allele defined by conventional serology.
Publisher: Frontiers Media SA
Date: 30-06-2017
Publisher: The American Association of Immunologists
Date: 15-01-2003
DOI: 10.4049/JIMMUNOL.170.2.805
Abstract: Granzyme B (grB) is a serine proteinase released by cytotoxic lymphocytes (CLs) to kill abnormal cells. GrB-mediated apoptotic pathways are conserved in nucleated cells hence, CLs require mechanisms to protect against ectopic or misdirected grB. The nucleocytoplasmic serpin, proteinase inhibitor 9 (PI-9), is a potent inhibitor of grB that protects cells from grB-mediated apoptosis in model systems. Here we show that PI-9 is present in CD4+ cells, CD8+ T cells, NK cells, and at lower levels in B cells and myeloid cells. PI-9 is up-regulated in response to grB production and degranulation, and associates with grB-containing granules in activated CTLs and NK cells. Intracellular complexes of PI-9 and grB are evident in NK cells, and overexpression of PI-9 enhances CTL potency, suggesting that cytoplasmic grB, which may threaten CL viability, is rapidly inactivated by PI-9. Because dendritic cells (DCs) acquire characteristics similar to those of target cells to activate naive CD8+ T cells and therefore may also require protection against grB, we investigated the expression of PI-9 in DCs. PI-9 is evident in thymic DCs (CD3−, CD4+, CD8−, CD45+), tonsillar DCs, and DC subsets purified from peripheral blood (CD16+ monocytes and CD123+ plasmacytoid DCs). Furthermore, PI-9 is expressed in monocyte-derived DCs and is up-regulated upon TNF-α-induced maturation of monocyte-derived DCs. In conclusion, the presence and subcellular localization of PI-9 in leukocytes and DCs are consistent with a protective role against ectopic or misdirected grB during an immune response.
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
DOI: 10.1371/JOURNAL.PPAT.1009214
Abstract: The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected in iduals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed in iduals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p .001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.
Publisher: Oxford University Press (OUP)
Date: 07-02-2017
Publisher: Future Medicine Ltd
Date: 2010
DOI: 10.2217/HIV.09.59
Abstract: Members of the Australasian Society for HIV Medicine (ASHM) include doctors, scientists, social scientists, epidemiologists, nurses and other allied health professionals who work in the field of HIV medicine, and the annual ASHM conference is targeted towards this membership. Furthermore, the ASHM has strong partnerships across the Asia and Pacific regions and, therefore, doctors, social researchers, nongovernment organizations and groups representing people living with HIV/AIDS from countries from the Asia and Pacific regions were well represented. The conference was jointly funded by the Australian Government, Queensland and Western Australia State Health Departments and the pharmaceutical industry, and was organized around four themes: understanding and identifying HIV: basic science, biology and pathogenesis managing HIV: clinical management and the the experience of living with HIV preventing HIV and HIV in populations.
Publisher: Oxford University Press (OUP)
Date: 02-1996
DOI: 10.1002/JLB.59.2.158
Abstract: Dendritic cells (DCs) are a distinct lineage of white cells that arise from CD34+ progenitors in the bone marrow. DCs exhibit many specializations that lead to efficient antigen capture and presentation to T cells, both CD4+ helpers and CD8+ killers. In several human tissues, DCs express the CD4 receptor for HIV-1. Some early reports described the explosive infection of blood-derived DCs by HIV-1 and a severe compromise of their presenting function. In contrast, other studies described active HIV-1 replication when DCs were interacting with CD4+ T cells. This productive infection could begin with a low viral burden in DCs but required that the DCs retain their normal binding and stimulatory function for T cells. In this review we first summarize those features of the DC system that seem pertinent to HIV-1 infection. Then we consider the current literature on the interaction of HIV-1 with DCs, from several different tissues, in HIV-1-infected patients or following challenge with HIV-1 in vitro. The literature leads to the hypothesis that HIV-1 infection is a battleground in which DCs could be leading both of the armies, the aggressor that promotes HIV-1 replication from relatively small numbers of infected cells and the defender that mediates T cell-dependent resistance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2007
Publisher: American Society for Microbiology
Date: 28-02-2020
DOI: 10.1128/JVI.01736-19
Abstract: In people living with HIV (PLWH) on suppressive ART, latent HIV can be found in a erse range of CD4 + T cells, including quiescent naive and central memory cells that are typically difficult to infect in vitro . It is currently unclear how latency is established in these cells in vivo . We show that in CD4 + T cells from PLWH on suppressive ART, the use of the coreceptor CXCR4 was prevalent among viruses lified from naive and central memory CD4 + T cells. Furthermore, we found that expanded numbers of identical viral sequences were most common in the effector memory population, and these identical sequences were also found in multiple different CD4 + T cell subsets. Our results help to shed light on how a range of CD4 + T cell subsets come to harbor HIV DNA, which is one of the major barriers to eradicating the virus from PLWH.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-04-2005
Publisher: Wiley
Date: 27-10-2021
Abstract: An increasing number of empirical studies aim to quantify in idual variation in demographic parameters because these patterns are key for evolutionary and ecological processes. Advanced approaches to estimate in idual heterogeneity are now using a multivariate normal distribution with correlated in idual random effects to account for the latent correlations among different demographic parameters occurring within in iduals. Despite the frequent use of multivariate mixed models, we lack an assessment of their reliability when applied to Bernoulli variables. Using simulations, we estimated the reliability of multivariate mixed effect models for estimating correlated fixed in idual heterogeneity in demographic parameters modelled with a Bernoulli distribution. We evaluated both bias and precision of the estimates across a range of scenarios that investigate the effects of life‐history strategy, levels of in idual heterogeneity and presence of temporal variation and state dependence. We also compared estimates across different s ling designs to assess the importance of study duration, number of in iduals monitored and detection probability. In many simulated scenarios, the estimates for the correlated random effects were biased and imprecise, which highlight the challenge in estimating correlated random effects for Bernoulli variables. The amount of fixed among‐in idual heterogeneity was frequently overestimated, and the absolute value of the correlation between random effects was almost always underestimated. Simulations also showed contrasting performances of mixed models depending on the scenario considered. Generally, estimation bias decreases and precision increases with slower pace of life, large fixed in idual heterogeneity and large s le size. We provide guidelines for the empirical investigation of in idual heterogeneity using correlated random effects according to the life‐history strategy of the species, as well as, the volume and structure of the data available to the researcher. Caution is warranted when interpreting results regarding correlated in idual random effects in demographic parameters modelled with a Bernoulli distribution. Because bias varies with s ling design and life history, comparisons of in idual heterogeneity among species is challenging. The issue addressed here is not specific to demography, making this warning relevant for all research areas, including behavioural and evolutionary studies.
Publisher: Oxford University Press (OUP)
Date: 09-1994
DOI: 10.1002/JLB.56.3.304
Abstract: The role of the leukocyte integrins in the infection of cells by HIV-1 or in the progression of AIDS-related disease is of continuing interest. Using a duallabeling flow cytometric method, we determined the level of expression of the leukocyte integrins and intercellular adhesion molecule 1 (ICAM-1) on monocytes and lymphocytes from HIV-1-infected and uninfected in iduals. The mean fluorescence of CD18 on lymphocytes and CD11c on monocytes of HIV-1-infected subjects was significantly higher than for the control group (P=.008 and.014, respectively). There was a trend toward higher fluorescence of CD11a on lymphocytes from HIV-1-infected subjects compared with cells from the control group (P=.089). Integrin expression on lymphocytes or monocytes from HIV-infected in iduals did not correlate with their CD4 lymphocyte number. However, the mean fluorescence associated with ICAM-1 on monocytes and CD11a and CD18 expression on lymphocytes was related to clinical stage of disease. J. Leukoc. Biol. 56: 304–309 1994.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-06-1995
Abstract: The human immunodeficiency virus 1 (HIV-1) replicates more efficiently in T-cell lines expressing T-cell receptors derived from certain V beta genes, V beta 12 in particular, suggesting the effects of a superantigen. The targeted V beta 12 subset was not deleted in HIV-1-infected patients. It was therefore possible that it might represent an in vivo viral reservoir. Viral load was assessed by quantitative PCR with gag primers and with an infectivity assay to measure competent virus. It was shown that the tiny V beta 12 subset (1-2% of T cells) often has a higher viral load than other V beta subsets in infected patients. Selective HIV-1 replication in V beta 12 cells was also observed 6-8 days after in vitro infection of peripheral blood lymphocytes from normal, HIV-1 negative donors. Viral replication in targeted V beta subsets may serve to promote a biologically relevant viral reservoir.
Publisher: Springer Science and Business Media LLC
Date: 04-1990
DOI: 10.1007/BF00204897
Location: Australia
Location: Australia
No related grants have been discovered for Paul Urquhart Cameron.