ORCID Profile
0000-0002-0330-8241
Current Organisations
The Peter Doherty Institute for Infection and Immunity
,
Monash University
,
University of Melbourne
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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: Springer Science and Business Media LLC
Date: 2007
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: Wiley
Date: 12-2003
DOI: 10.1046/J.1440-1711.2003.01191.X
Abstract: Analysing T-cell receptor excision circle numbers in healthy in iduals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for in iduals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older in iduals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for in iduals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.
Publisher: American College of Physicians
Date: 2022
DOI: 10.7326/L21-0297
Publisher: Public Library of Science (PLoS)
Date: 04-03-2020
Publisher: Elsevier BV
Date: 07-2014
Publisher: American Society for Microbiology
Date: 10-2009
DOI: 10.1128/CMR.00015-09
Abstract: Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For ex le, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal s le sets and clinical presentations are required to illuminate the erse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.
Publisher: Mary Ann Liebert Inc
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 17-08-2023
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: Wiley
Date: 12-2019
DOI: 10.1002/JIA2.25425
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-01-2014
Publisher: American Society for Microbiology
Date: 08-2004
DOI: 10.1128/JCM.42.8.3809-3812.2004
Abstract: We report a rapid and accurate real-time PCR-based method to quantify wild-type and lamivudine-resistant hepatitis B virus by using a common forward primer paired with different reverse primers. Excellent concordance was demonstrated between sequencing and the discriminatory real-time assay however, a mixture of quasispecies was more frequently detected by discriminatory real-time PCR.
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: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2005
DOI: 10.1097/01.QAI.0000173460.75322.93
Abstract: Virologic failure on continuous antiretroviral therapy (ART) is associated with variable changes in CD4 T-cell counts: peripheral CD4 T-cell counts decrease in conjunction with a resurgence of plasma virus (nonresponders) or remain stable or continue to increase despite ongoing virus replication (discordant responders). This study found that HIV-1 isolated from nonresponders had significantly greater replicative capacity in activated peripheral blood mononuclear cells (PBMCs) as well as an enhanced ability to induce apoptosis in both HIV-1-infected and HIV-1-uninfected CD4 T cells compared with virus isolated from discordant responders. Enhanced replicative capacity in PBMCs of virus isolated from nonresponders was inhibited by AMD3100, a CXCR4 antagonist. Virus quasispecies isolated from PBMCs from nonresponders used both CC chemokine receptor 5 (CCR5) and CX chemokine receptor 4 (CXCR4) for entry, in contrast to virus isolated from PBMCs from discordant responders, which predominantly used CCR5. In contrast, virus isolated from plasma from both groups predominantly used CCR5. In summary, although drug resistance may lead to impaired viral fitness, the capacity of virus quasispecies from PBMCs to use CXCR4 may have significant consequences on viral replicative capacity and potentially on clinical outcome.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 05-2018
Publisher: Oxford University Press (OUP)
Date: 30-03-2016
Publisher: Public Library of Science (PLoS)
Date: 30-11-2017
Publisher: Wiley
Date: 27-08-2022
DOI: 10.1111/JMP.12613
Abstract: One strategy to eliminate latently infected cells that persist in people with HIV on antiretroviral therapy is to activate virus transcription and virus production to induce virus or immune‐mediated cell death. This is called latency reversal. Despite clear activity of multiple latency reversal agents in vitro, clinical trials of latency‐reversing agents have not shown significant reduction in latently infected cells. We review new insights into the biology of HIV latency and discuss novel approaches to enhance the efficacy of latency reversal agents.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-06-2017
Publisher: CSIRO Publishing
Date: 2008
DOI: 10.1071/SH07094
Abstract: Background: Rates of HIV in New South Wales (NSW) have been stable, but have increased significantly in other Australian states. The reasons for this are unknown and may be associated with differences in the management of sexually transmissible infections (STI) and HIV in different states in Australia. Our aim was to determine if the use of suppressive treatment for genital herpes, the treatment of HIV or STI screening practices were different between states in Australia. Methods: This study was a cross-sectional survey of medical practitioners who are S100 prescribers and members of the Australian Society for HIV Medicine. Results: In general, there were no differences between the clinical practices of practitioners in NSW and other states except that in NSW fewer practitioners tested HIV-positive men who have sex with men (MSM) for syphilis annually (NSW 78% v. others 87%, P = 0.04) or treated MSM with advanced HIV disease (CD4 150 × 106 cells L–1) with acicylovir in the absence of herpes simplex virus (HSV) (NSW 4% v. others 13%, P = 0.03), and more practitioners in NSW tested HIV-negative MSM for HSV type-specific serology (NSW 21% v. others 11%, P = 0.02). Conclusions: It is unlikely that the minor differences in HSV and HIV treatment or STI screening practices among practitioners in NSW and other Australian states explains the differences in HIV notifications between these two areas.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2021
DOI: 10.1038/S41467-021-24673-W
Abstract: Health systems have improved their abilities to identify, diagnose, treat and, increasingly, achieve viral suppression among people living with HIV (PLHIV). Despite these advances, a higher burden of multimorbidity and poorer health-related quality of life are reported by many PLHIV in comparison to people without HIV. Stigma and discrimination further exacerbate these poor outcomes. A global multidisciplinary group of HIV experts developed a consensus statement identifying key issues that health systems must address in order to move beyond the HIV field’s longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for PLHIV throughout their lives.
Publisher: BMJ
Date: 27-11-2014
DOI: 10.1136/GUTJNL-2014-308211
Abstract: Unique immunological changes occur during pregnancy the impact of which, on virological and biochemical markers of hepatitis B infection is not well established. Rapid changes in the immunological profile post partum and consequent rebound of the inflammatory response may result in hepatic flares. Women with chronic hepatitis B were recruited during pregnancy into this observational study. Demographic and clinical data were collected together with virological and biochemical parameters at two time points during pregnancy (early and late) and two time points post partum (between 6 weeks and 12 weeks and at 12 months). Outcomes analysed included changes in HBV DNA, hepatitis B e antigen (HBeAg) status and flares of hepatitis. One hundred and twenty-six women were recruited. Twenty-seven women out of 108 with postpartum bloods (25%) met our definition of a postpartum flare (ALT range 38-1654). Using univariate analysis HBeAg status, younger age, gravida and parity were associated with a flare. On multivariate analysis HBeAg positivity at baseline fell just outside of statistical significance in predicting a postpartum flare (p=0.051). 25% of women with chronic hepatitis B will demonstrate increased liver inflammation in the postpartum period. This is usually asymptomatic and resolves spontaneously. This is more likely if the woman is HBeAg-positive at baseline (2.56 times the risk), although flares also commonly occur in HBeAg-negative women.
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: Springer Science and Business Media LLC
Date: 14-03-2018
DOI: 10.1007/S11908-018-0610-4
Abstract: Immune monitoring to determine when and how the recovery of cytomegalovirus (CMV)-specific T-cells occurs post-transplantation may help clinicians to risk stratify in iduals at risk of complications from CMV. We aimed to review all recent clinical studies using CMV immune monitoring in the pre- and post-transplant setting including the use of recently developed standardized assays (Quantiferon-CMV and the CMV ELISPOT) to better understand in whom, when, and how immune monitoring is best used. Pre-transplant assessment of CMV immunity in solid-organ transplant recipients where CMV seropositive recipients had undetectable cell-mediated responses despite past immunity has shown that they are at a much higher risk of developing CMV reactivation. Post-transplant CMV immune monitoring can guide (shorten or prolong) the duration of antiviral prophylaxis, identify recipients at risk of post-prophylaxis CMV disease, and predict recurrent CMV reactivation. Thus, CMV immune monitoring, in addition to current clinical and DNA-based monitoring for CMV, has the potential to be incorporated into routine clinical care to better improve CMV management in both the stem and solid-organ transplant population.
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: Elsevier BV
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-04-2006
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.VIROL.2005.04.034
Abstract: The mechanisms underlying the pathogenicity of CCR5-restricted (R5) human immunodeficiency virus type-1 (HIV-1) strains are incompletely understood. Acquisition or enhancement of macrophage (M)-tropism by R5 viruses contributes to R5 HIV-1 pathogenesis. In this study, we show that M-tropic R5 viruses isolated from in iduals with acquired immunodeficiency syndrome (late R5 viruses) require lower levels of CD4/CCR5 expression for entry, have decreased sensitivity to inhibition by the entry inhibitors TAK-779 and T-20, and have increased sensitivity to neutralization by the Env MAb IgG1b12 compared with non-M-tropic R5 viruses isolated from asymptomatic, immunocompetent in iduals (early R5 viruses). Augmenting CCR5 expression levels on monocyte-derived macrophages via retroviral transduction led to a complete or marginal restoration of M-tropism by early R5 viruses, depending on the viral strain. Thus, reduced CD4/CCR5 dependence is a phenotype of R5 HIV-1 associated with M-tropism and late stage infection, which may affect the efficacy of HIV-1 entry inhibitors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2017
Publisher: Public Library of Science (PLoS)
Date: 25-08-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: American Society for Microbiology
Date: 15-12-2017
DOI: 10.1128/JVI.01395-17
Abstract: A number of treatment strategies are currently being developed to promote antiretroviral therapy-free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work, we use a stochastic model to show that a treatment that achieves a 1-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first 3 months. Given quarterly viral testing intervals, this leads to an expected 39 (95% uncertainty interval [UI], 22 to 69) heterosexual transmissions and up to 262 (95% UI, 107 to 534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the “useful” or optimal length of antiretroviral therapy-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission versus the risk of treatment failure (viral recrudescence) and the need for retreatment. To minimize drug exposure, we found that the optimal target of antilatency interventions is a 1,700-fold reduction in the size of the reservoir, which leads to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally, we show that when shorter periods are targeted, there is a real probability of viral transmission occurring between tests for viral rebound. IMPORTANCE Current treatment of HIV involves patients taking antiretroviral therapy to ensure that the level of virus remains very low or undetectable. Continuous therapy is required, as the virus persists in a latent state within cells, and when therapy is stopped, the virus rebounds, usually within 2 weeks. A major question is how to reduce the amount of persistent virus and therefore allow a delay or remission until the virus returns after ceasing therapy. In this work, we consider the probability that HIV will still rebound even after this reduction and ask what the likelihood of viral transmission would be in this case.
Publisher: Oxford University Press (OUP)
Date: 25-12-2020
DOI: 10.1093/NAR/GKZ1181
Abstract: Tat protein is essential to fully activate HIV transcription and processing of viral mRNA, and therefore determines virus expression in productive replication and the establishment and maintenance of latent infection. Here, we used thermodynamic and structure analyses to define a highly conserved sequence-structure in tat mRNA that functions as Tat IRES modulator of tat mRNA (TIM-TAM). By impeding cap-dependent ribosome progression during authentic spliced tat mRNA translation, TIM-TAM stable structure impacts on timing and level of Tat protein hence controlling HIV production and infectivity along with promoting latency. TIM-TAM also adopts a conformation that mediates Tat internal ribosome entry site (IRES)-dependent translation during the early phases of infection before provirus integration. Our results document the critical role of TIM-TAM in Tat expression to facilitate virus reactivation from latency, with implications for HIV treatment and drug development.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/SH16165
Abstract: Background: Progressively sensitive assays for plasma HIV RNA have led to increased detection of plasma HIV RNA between 20 and 200 copies/ml, known as low level viremia (LLV) when recurrent or persistent, in HIV-infected patients on antiretroviral therapy (ART). The aim of this study was to determine outcomes following initial detection of LLV in an Australian cohort. Methods: A retrospective study using the HIV Service Database (Alfred Hospital) included all patients on ART who recorded plasma HIV RNA 20–200 copies/mL following prior virological suppression (viral load (VL) HIV RNA copies/mL) over 2 years (2010 to 2012), with follow-up to June 2013. Factors associated with subsequent virological outcome were assessed via univariate and multivariate analysis. Results: Of 919 patients managed by The Alfred HIV service, 207 (22.5%) met inclusion criteria. Mean age was 48.8 years, 91.3% were male. During follow-up, 54% patients recorded no further HIV RNA 20–200 copies/mL (viral blip) 39% had recurrent or persistent VL 20–200 copies/mL (LLV) and 7% progressed to virological failure with VL copies/mL. Factors associated with LLV included co-morbid type 2 diabetes, shorter prior virological suppression and lower nadir CD4 cell count. Clinician management of VL 20–200 copies/mL was generally conservative, with infrequent requests for genotypic analysis (3.3% cases) or change in ART ( % cases). Conclusions: LLV following virological suppression is common, and occurred as an isolated viral blip in half the patients. Those patients with persistent or recurrent LLV had higher rates of type 2 diabetes, shorter prior virological suppression and lower nadir CD4 cell count.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2010
DOI: 10.1002/HEP.23571
Abstract: Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71 HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP) recore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.
Publisher: American Society for Microbiology
Date: 05-2017
DOI: 10.1128/JVI.02092-16
Abstract: Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment. IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.
Publisher: Oxford University Press (OUP)
Date: 05-07-2017
DOI: 10.1093/CID/CIX598
Publisher: Wiley
Date: 31-03-2019
DOI: 10.5694/MJA2.50114
Publisher: Oxford University Press (OUP)
Date: 18-01-2011
DOI: 10.1093/CID/CIQ167
Publisher: Elsevier BV
Date: 12-2015
Publisher: Baishideng Publishing Group Inc.
Date: 2012
DOI: 10.4254/WJH.V4.I3.91
Publisher: SAGE Publications
Date: 2014
DOI: 10.3851/IMP2673
Abstract: Vitamin D insufficiency plays an important role in the development of fibrosis in chronic liver disease. This was a cross-sectional study from Thailand. Liver fibrosis was assessed by transient elastography. Serum 25 hydroxyvitamin D (25[OH]D) ng/ml was defined as hypovitaminosis D. 25(OH)D was assessed prior to and following tenofovir disoproxil fumarate (TDF). Factors related to 25(OH)D levels were determined by logistic regression analysis. A total of 158 HIV–HBV-coinfected patients (32% female, median age 43 years) were included. Overall, liver disease was mild with 13.4% having a fibrosis score (FS) of 7.1–14 kPa and 2% with a FS kPa. Median (IQR) duration on TDF was 5 years (4–7). The median estimated glomerular filtration rate was 96.9 ml/min/1.73 m 2 . The median (IQR) serum 25(OH)D levels prior to and following TDF were 24.8 ng/ml (21.3–30.6) and 22.8 ng/ml (18.0–27.7), respectively P≤0.001). The proportion of patients with hypovitaminosis D significantly increased from 72.2% (95% CI 64.7, 78.6) prior to TDF to 84.2% (95% CI 77.7, 89.0) after taking TDF ( P=0.01). Factors associated with hypovitaminosis D by multivariate analysis were female sex (adjusted OR 3.8, 95% CI 1.1, 13.7 P=0.038) and duration of antiretroviral therapy (ART) years (OR 3.3, 95% CI 1.2, 8.8 P=0.017). Vitamin D levels were not associated with significant liver fibrosis. Although our HIV–HBV-coinfected patients live in the tropics, there was a high prevalence of hypovitaminosis D, especially in female patients and those receiving prolonged ART. Since HIV–HBV-coinfection requires long-term use of the HBV-active drug, TDF, which can also contribute to bone loss, routine vitamin D assessment and supplementation as necessary should be considered.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.DIAGMICROBIO.2014.09.006
Abstract: We determined the susceptibility of 102 clinical isolates Cryptococcus neoformans from Durban, South Africa, to hotericin B, fluconazole, flucytosine, and voriconazole using broth microdilution (BMD) according to the Clinical and Laboratory Standards Institute M27-A3 document and compared these results with Etest and Vitek 2(®). Essential agreement (EA) of Etest and Vitek 2(®) compared to BMD was determined. Low MICs that were below the epidemiological cutoff values of the 4 antifungal agents tested were demonstrated by all isolates. The EA of Etests for fluconazole, hotericin, and voriconazole was 95.1%, 83.3%, and 91.2%, respectively, and for Vitek 2(®) EA for fluconazole, hotericin, and flucytosine was 97.1%, 95.1%, and 97.1%, respectively. The Vitek 2(®) showed good agreement with BMD and is a suitable alternative. Etests demonstrated good EA for azoles only. Clinical cryptococcal isolates from Durban remain susceptible to current recommended antifungal therapy.
Publisher: Public Library of Science (PLoS)
Date: 09-12-2016
Publisher: Case Western Reserve University
Date: 16-08-2016
Abstract: With the advent and stunning success of combination antiretroviral therapy (ART) to prolong and improve quality of life for persons with HIV infection, HIV research has been afforded the opportunity to pivot towards studies aimed at finding “a cure.” The mere idea that cure of HIV might be possible has energized researchers and the community towards achieving this goal. Funding agencies, both governmental and private, have targeted HIV cure as a high priority many in the field have responded to these initiatives and the cure research agenda is robust.In this “salon” two editors of Pathogens and Immunity, Michael Lederman and Daniel Douek ask whether curing HIV is a realistic, scalable objective. We start with an overview perspective and have asked a number of prominent HIV researchers to add to the discussion.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2008
Publisher: Wiley
Date: 2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2017
Publisher: Oxford University Press (OUP)
Date: 16-07-2018
Abstract: Initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected in iduals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated. We compared plasma levels of immunoglobulins, C. neoformans glucuronoxylomannan (GXM) capsule-specific and laminarin (Lam)-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not, and evaluated associations of these parameters with risk of C-IRIS. Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P = .0003), Lam-IgM (P = .0005), Lam-IgG (P = .002), and GXM-IgM (P = .002) independent of age, sex, HIV viral load, CD4+ T-cell count, and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells. Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2003
DOI: 10.1097/00002030-200307250-00009
Abstract: To determine the prevalence of hepatitis B virus (HBV) genotypic resistance to lamivudine, identify risk factors associated with lamivudine resistance, and characterize the pattern of HBV polymerase mutations in patients co-infected with HIV. Retrospective cross-sectional study. Thirty-three chronic HBV-infected patients were identified from a cohort of 1719 HIV-infected in iduals. Patient information was collected from case records, HBV DNA was measured on stored serum by polymerase chain reaction, and positive s les underwent sequencing of HBV polymerase, basal core promoter and precore regions. Three groups of patients were identified: group 1 were viraemic in the absence of lamivudine-resistance mutations, group 2 were viraemic in association with lamivudine-resistance mutations, and group 3 were not viraemic. Group 2 patients with lamivudine-resistant mutations had significantly higher HBV-DNA viral loads but did not differ in duration of lamivudine therapy, HBV genotype, HIV viral load or CD4 cell count compared with patients with wild-type HBV. Group 2 in iduals also demonstrated significantly higher serum alanine aminotransferase (ALT) levels than group 1, who were higher than group 3. Unique mutations were detected in HBV polymerase, including rtV173L plus rtL180M plus rtM204V, which occurred in three patients. This virus has the in-vitro characteristics of a 'vaccine escape' mutant of HBV. Genotypic HBV lamivudine resistance was found in 39% of HIV-HBV co-infected in iduals treated with lamivudine as part of highly active antiretroviral therapy. These patients exhibited significantly elevated HBV viral loads and serum ALT, and three were infected with a lamivudine-resistant HBV strain that was potentially transmissible to HBV-vaccinated in iduals.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.CLIM.2010.07.003
Abstract: Severe immunodeficiency during primary human immunodeficiency virus (HIV) infection is unusual. Here, we characterized viral and immunological parameters in a subject presenting with Pneumocystis jirovecii pneumonia in the setting of prolonged primary HIV illness and delayed seroconversion. HIV antibody was only detected by enzyme-linked immunosorbent assay 12 months after presentation, and Western blot profiles remain indeterminate. Isolated virus was of R5 phenotype, exhibited poor viral fitness, but was otherwise unremarkable. Analysis of HIV antibody isotypes showed failure to mount a detectable HIV IgG response over nearly 2 years of infection, in particular IgG(1)- and IgG(3)-specific responses, despite normal responses to common infections and vaccines. Genetic analysis demonstrated homozygosity for part of an MHC haplotype containing susceptibility genes for common variable immunodeficiency (CVID) syndrome and other antibody deficiency disorders. Thus, a primary disorder of specific antibody production may explain exceptionally slow antibody development in an otherwise severe seroconversion illness. This highlights the need for multiparameter testing, in particular use of a fourth generation HIV test, for confirming HIV infection and underscores the importance of host factors in HIV pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2023
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: Oxford University Press (OUP)
Date: 02-04-2020
DOI: 10.1093/OFID/OFAA115
Abstract: Hepatitis C virus (HCV) coinfection among people with human immunodeficiency virus (HIV) might perturb immune function and HIV persistence. We aimed to evaluate the impact of HCV clearance with direct-acting antivirals (DAAs) on immune activation and HIV persistence in HIV/HCV-coinfected in iduals on antiretroviral therapy (ART). In a prospective observational study, ART-treated participants with HIV/HCV coinfection received sofosbuvir/daclatasvir ± ribavirin (n = 19). Blood s les were collected before DAA therapy, at the end of treatment, and 12 months after DAA termination (12MPT). T- and natural killer (NK)-cell phenotype, soluble plasma factors, cell-associated (CA)-HIV deoxyribonucleic acid (DNA) forms (total, integrated, 2LTR), CA-unspliced (US) and multiple-spliced ribonucleic acid (RNA), and plasma HIV RNA were evaluated. Hepatitis C virus clearance was associated with (1) a downmodulation of activation and exhaustion markers in CD4+, CD8+ T, and NK cells together with (2) decreased plasma levels of Interferon gamma-induced protein 10 (IP10), interleukin-8 (IL-8), soluble (s)CD163 and soluble intercellular adhesion molecule (sICAM). Cell-associated US HIV RNA was significantly higher at 12MPT compared to baseline, with no change in HIV DNA or plasma RNA. Elimination of HCV in HIV/HCV-coinfected in iduals alters immune function and the transcriptional activity of latently infected cells. This report provides insights into the effects of HCV coinfection in HIV persistence and regards coinfected subjects as a population in which HIV remission might prove to be more challenging.
Publisher: Elsevier BV
Date: 2016
Publisher: Informa UK Limited
Date: 14-05-2013
DOI: 10.4161/HV.23800
Publisher: Elsevier BV
Date: 03-2020
Publisher: Public Library of Science (PLoS)
Date: 04-11-2014
Publisher: Elsevier
Date: 2006
Publisher: Public Library of Science (PLoS)
Date: 05-12-2013
Publisher: American Society for Microbiology
Date: 08-2006
DOI: 10.1128/JCM.02544-05
Abstract: The performance characteristics of the RealART and Molecular Beacons assays were compared with those of the Digene Hybrid Capture II assay (ultrasensitive). The results of the RealART and Digene Hybrid assays were related ( r = 0.94 P 0.001) and erged by 2 orders of magnitude. The RealART assay can be used to effectively monitor serum hepatitis B virus DNA levels.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2017
Publisher: Elsevier BV
Date: 05-0006
Publisher: Public Library of Science (PLoS)
Date: 14-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-08-2008
DOI: 10.1002/HEP.22462
Abstract: Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is associated with considerable liver disease morbidity and mortality. Emerging HIV epidemics in areas of high HBV endemicity such as Asia are expanding the population with HIV/HBV coinfection. Limited randomized trial data exist to support current guidelines for HBV combination therapy in HIV/HBV coinfection. The objective of this prospective randomized clinical trial was to compare the strategy of HBV monotherapy with lamivudine (LAM) or tenofovir disoproxil fumarate (TDF) versus HBV combination therapy with LAM/TDF in antiretroviral-naïve HIV/HBV-coinfected subjects in Thailand. Thirty-six HIV/HBV-coinfected subjects initiating highly active antiretroviral therapy (HAART) were randomized to either LAM (arm 1), TDF (arm 2), or LAM/TDF (arm 3) as HBV-active drugs within HAART. At week 48, time-weighted area under the curve analysis revealed that the median HBV DNA reduction from baseline was 4.07 log(10) c/mL in arm 1, 4.57 log(10) c/mL in arm 2, and 4.73 log(10) c/mL in arm 3 (P = 0.70). HBV DNA suppressed to 3 log(10) c/mL at week 48 and in early resistance development. This study confirms current treatment guidelines that recommend a TDF-based regimen as the treatment of choice for HIV/HBV coinfection, but does not demonstrate any advantage of HBV combination therapy in this short-term setting.
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: SAGE Publications
Date: 08-2010
DOI: 10.3851/IMP1645
Abstract: Therapy for chronic hepatitis B with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) is currently recommended for HIV–HBV coinfection. However, there is limited randomized data on the efficacy of combined therapy with TDF and FTC, especially in antiretroviral (ARV)-naive patients. This was a prospective randomized clinical trial comparing the efficacy of HBV monotherapy with FTC versus TDF/FTC combination therapy in ARV-naive HIV– HBV coinfection. HIV–HBV-coinfected patients initiating ARV were randomized to either FTC/zidovudine/efavirenz (EFV n=6) or TDF/FTC/EFV ( n=10). The primary end point was the time-weighted area under the curve (TWAUC) of HBV DNA at 48 weeks. The median baseline CD4 + T-cell count was 64 cells/μl (interquartile range [IQR] 36–172), plasma HIV type-1 RNA was 4.90 log 10 copies/ml (IQR 4.58–5.44) and plasma HBV DNA was 8.76 log 10 copies/ml (IQR 8.45–8.82). A total of 11/16 (69%) patients were hepatitis B e antigen (HBeAg)-positive. The median TWAUC decrease in HBV DNA was -5.32 log 10 copies/ml in the TDF/FTC group compared with -3.25 log 10 copies/ml in the FTC group ( P=0.03). At week 48, 90% of the TDF/FTC group and 33% of the FTC group had plasma HBV DNA copies/ ml ( P=0.036, intention-to-treat analysis). HBeAg loss was observed in 4/11 (36%) HBeAg-positive patients. Hepatic fares were observed in 3/16 (19%) of patients. TDF/FTC combination therapy resulted in a significantly greater decrease in HBV DNA than FTC monotherapy, with a greater proportion of patients with undetectable HBV DNA at week 48. Our study supports the current recommendation of ARV containing TDF/FTC as the treatment of choice for patients with HIV–HBV coinfection.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2016
Publisher: Oxford University Press (OUP)
Date: 11-2004
DOI: 10.1086/424851
Abstract: The effect that tuberculosis (TB) has on human immunodeficiency virus (HIV) disease progression is not clearly understood. In an observational cohort study of HIV-infected adults in South Africa, baseline and final HIV load were compared between in iduals who experienced an episode of TB (n=30) during follow-up and control subjects (n=56) matched by baseline CD4 cell count and follow-up time linear regression modeling was used to control for confounding. Mean HIV load was higher in the TB group than in the non-TB control group for both baseline (4.73 vs. 4.24 log(10) copies/mL P=.003) and final values (5.02 vs. 4.34 log(10) copies/mL P<.001). After adjustment for baseline HIV load and World Health Organization HIV stage, the difference in final HIV load was 0.24 log(10) copies/mL (95% confidence interval, -0.01 to 0.50 log(10) copies/mL P=.06). Poor prognosis for HIV-infected in iduals after TB may be due to preexisting high HIV load rather than to the TB event itself. An episode of TB was associated with a small adjusted increase in HIV load at the end of the study--an increase that would not be regarded as clinically significant in an in idual but could have some effect on HIV disease progression or HIV transmission at the population level. Prevention of TB is important for the reduction of HIV-related morbidity and mortality however, antiretroviral therapy is required to have a major effect on survival in in iduals with HIV disease.
Publisher: Wiley
Date: 14-05-2012
DOI: 10.1002/JMV.23236
Abstract: Histological parameters were assessed in liver biopsies (n = 48) performed in patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in order to evaluate factors which were associated with significant liver disease. Necroinflammation and fibrosis was scored by the Ishak classification system, and binary logistic regression analysis was used to assess HIV and antiretroviral-related determinants of necroinflammation and fibrosis. A total of 46 biopsies were included 33 were from HIV-positive patients co-infected with HCV and 15 biopsies were from HIV-positive patients co-infected with HBV. One HIV-positive patient was co-infected with HBV and HCV. Median biopsy inflammatory grade for the cohort was 8.5 (IQR 6-10), the median fibrosis Stage 2 (IQR 1.8-4), and the median steatosis score was 1 (IQR 0-2). At the univariate level, HIV-related variables that were significantly associated with more severe biopsy changes were higher HIV RNA at the time of biopsy (associated with inflammatory Grade 10+ P = 0.018) and any exposure to didanasine (ddI) or stavudine (D4T associated with fibrosis Stage 3+ P = 0.022). HIV RNA at the time of biopsy remained significant at the multivariate level. Patients with HIV hepatitis co-infection in this cohort had surprisingly mild changes in liver histology, and there were no statistically significant differences between biopsy results in HBV compared to HCV co-infection. The association between HIV RNA and necroinflammation supports current recommendations for earlier initiation of HAART in patients with HIV-hepatitis co-infection.
Publisher: Wiley
Date: 11-03-2009
DOI: 10.1111/J.1468-1293.2008.00675.X
Abstract: The aim of the study was to identify and characterize hepatitis B virus (HBV) polymerase gene mutations associated with ongoing HBV replication in HIV/HBV-coinfected in iduals receiving tenofovir (TDF). This retrospective cross-sectional study identified 28 HIV/HBV-coinfected in iduals who had received TDF for at least 3 months. All patients had s les available while receiving TDF (on-TDF), and 24 also had s les available prior to treatment (pre-TDF). Case records were reviewed to obtain clinical and virological data at the times of s ling (+/-3 months). The HBV DNA of all s les was lified using polymerase chain reaction (PCR), and the polymerase region of PCR-positive s les was sequenced and compared with reference HBV data. Of the pre-TDF s les, 15 of 24 (63%) were HBV PCR positive. Of the on-TDF s les, four of 28 (14%) were HBV PCR positive (mean time on TDF 13.5 months range 3-23 months). Lamivudine (3TC)-resistance mutations were detected in three of four (75%) of these viraemic s les. The previously identified putative TDF-resistance mutations, rtA194T+rtL180M+rtM204V, were not detected in any in idual. Unique mutations in the HBV polymerase gene associated with TDF resistance are rare in HIV/HBV coinfection. 3TC-resistance mutations persist and a significant proportion of patients are HBV PCR positive despite the addition of TDF.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2015
Publisher: Public Library of Science (PLoS)
Date: 02-06-2011
Publisher: Springer Science and Business Media LLC
Date: 20-04-2013
Abstract: The CCR5 antagonist maraviroc (MVC) inhibits human immunodeficiency virus type 1 (HIV-1) entry by altering the CCR5 extracellular loops (ECL), such that the gp120 envelope glycoproteins (Env) no longer recognize CCR5. The mechanisms of HIV-1 resistance to MVC, the only CCR5 antagonist licensed for clinical use are poorly understood, with insights into MVC resistance almost exclusively limited to knowledge obtained from in vitro studies or from studies of resistance to other CCR5 antagonists. To more precisely understand mechanisms of resistance to MVC in vivo , we characterized Envs isolated from 2 subjects who experienced virologic failure on MVC. Envs were cloned from subjects 17 and 24 before commencement of MVC (17-Sens and 24-Sens) and after virologic failure (17-Res and 24-Res). The Envs cloned during virologic failure showed broad ergence in resistance levels, with 17-Res Env exhibiting a relatively high maximal percent inhibition (MPI) of ~90% in NP2-CD4/CCR5 cells and peripheral blood mononuclear cells (PBMC), and 24-Res Env exhibiting a very low MPI of ~0 to 12% in both cell types, indicating relatively “weak” and “strong” resistance, respectively. Resistance mutations were strain-specific and mapped to the gp120 V3 loop. Affinity profiling by the 293-Affinofile assay and mathematical modeling using VERSA (Viral Entry Receptor Sensitivity Analysis) metrics revealed that 17-Res and 24-Res Envs engaged MVC-bound CCR5 inefficiently or very efficiently, respectively. Despite highly ergent phenotypes, and a lack of common gp120 resistance mutations, both resistant Envs exhibited an almost superimposable pattern of dramatically increased reliance on sulfated tyrosine residues in the CCR5 N-terminus, and on histidine residues in the CCR5 ECLs. This altered mechanism of CCR5 engagement rendered both the resistant Envs susceptible to neutralization by a sulfated peptide fragment of the CCR5 N-terminus. Clinical resistance to MVC may involve ergent Env phenotypes and different genetic alterations in gp120, but the molecular mechanism of resistance of the Envs studied here appears to be related. The increased reliance on sulfated CCR5 N-terminus residues suggests a new avenue to block HIV-1 entry by CCR5 N-terminus sulfopeptidomimetic drugs.
Publisher: Oxford University Press (OUP)
Date: 19-09-2011
Abstract: Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients. We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods. Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27 20.45, P = .724 and 9.43 cells/μL, -7.81 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA. The determinants of poor CD4(+) T-cell recovery following cART require further investigation. ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.
Publisher: AMPCo
Date: 04-2020
DOI: 10.5694/MJA2.50569
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: Ovid Technologies (Wolters Kluwer Health)
Date: 24-04-2011
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 06-2013
Publisher: Elsevier BV
Date: 11-2013
Publisher: Oxford University Press (OUP)
Date: 02-2009
DOI: 10.1086/595894
Publisher: Wiley
Date: 2018
DOI: 10.1111/IMJ.13673
Publisher: Elsevier BV
Date: 07-2018
Publisher: American Society for Microbiology
Date: 03-2005
DOI: 10.1128/JVI.79.5.3038-3051.2005
Abstract: Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in in iduals chronically infected with HBV compared to in iduals with self-limiting HBV infection or those on anti-HBV therapy. In in iduals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with erse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4 + and CD8 + T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers ( n = 34) were studied, including in iduals never treated for HBV infection ( n = 7), HBV-infected in iduals receiving anti-HBV therapy ( n = 13), and HIV-1-HBV-coinfected in iduals receiving anti-HBV therapy ( n = 14). CD4 + and CD8 + HBV-specific T-cell responses were more frequently detected and the CD8 + T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBV-specific T-cell response and HBV viral load. HBV-specific CD4 + and CD8 + T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8 + T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4 + T-cell responses were significantly reduced in HIV-1-HBV-coinfected in iduals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.
Publisher: Oxford University Press (OUP)
Date: 12-10-2021
DOI: 10.1093/CID/CIAA1539
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1086/597276
Abstract: The pathogenesis of and risk factors for hepatic flare (HF) after the initiation of hepatitis B virus (HBV)-active antiretroviral therapy (ART) in HIV/HBV-coinfected in iduals is not well understood. We studied HF in ART-naive HIV/HBV-coinfected in iduals in Thailand (n = 36) who were beginning HBV-active ART as part of a prospective clinical trial. HF was defined as an alanine aminotransferase (ALT) level>5 times the upper limit of normal or >200 IU/L higher than that at baseline. Immune mediators (interleukin [IL]-18, IL-2, IL-6, IL-8, IL-10, soluble CD26 [sCD26], sCD30, sCD8, CXCL-10, CCL-2, tumor necrosis factor-alpha, interferon [IFN]-gamma, and IFN-alpha) and activated NK cells were quantified. HBV DNA and ALT levels at baseline were higher in patients with HF (n=8) than in patients without HF (n=28) (P=.01). After the initiation of ART, CXCL-10 levels remained elevated in patients with HF but decreased in patients without HF (P<.01). sCD30 levels increased and were significantly higher at week 8 in patients with HF (P<.05). There was a positive correlation between levels of ALT and levels of CXCL-10, sCD30, CCL-2, and IL-18 at week 8 (the time of peak ALT level) but not at other time points. Elevated HBV DNA and ALT levels before the initiation of HBV-active ART are risk factors for HF. The pathogenesis of HF after the initiation of HBV-active ART is probably consistent with immune restoration disease.
Publisher: Elsevier BV
Date: 03-2021
Publisher: SAGE Publications
Date: 05-2013
DOI: 10.3851/IMP2720
Abstract: Interferon stimulated chemokine CXCL-10, interleukin (IL)-12 (p70) and IL-21 have been associated with HBsAg and HBeAg loss following treatment of HBV monoinfection. The aim of this study was to determine whether these factors were also associated with HBsAg and HBeAg loss in HIV–HBV-coinfected patients following HBV-active combination antiretroviral therapy (cART). HIV–HBV-coinfected patients with HBeAg seroconversion ( n=12 seroconverters [SC]) were compared to patients who did not seroconvert ( n=13 non-seroconverters [NSC]). CXCL-10, IL-12 and IL-21 (Luminex Bead Array, Life Technologies, Grand Island, NY, USA) were measured in plasma prior to initiation of HBV-active cART (baseline), at the time of seroconversion (T0) and at the closest time point before (T-1) and after (T+1) seroconversion. Levels of CXCL-10 declined significantly in all patients following HBV-active cART ( P .05 for both SC and NSC Kruskall-Wallis, Dunn's post-test). There was no difference between SC and NSC in the level of CXCL-10, IL-12 and IL-21 at any time point. We found no evidence that CXCL-10, IL-12 or IL-21 were associated with HBeAg seroconversion following HBV-active cART. Other immunological determinants should be explored in this setting.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2007
DOI: 10.1002/HEP.21482
Abstract: Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed in vitro using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-alpha) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-alpha production. This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Oxford University Press (OUP)
Date: 28-04-2012
DOI: 10.1093/NAR/GKS334
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41591-021-01590-5
Abstract: Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. HIV can integrate in the host genome and persist for the life span of the infected cell. These latently infected cells are not recognized as foreign because they are largely transcriptionally silent, but contain replication-competent virus that drives resurgence of the infection once ART is stopped. With a combination of immune activators, neutralizing antibodies, and therapeutic vaccines, some nonhuman primate models have been cured, providing optimism for these approaches now being evaluated in human clinical trials. In vivo delivery of gene-editing tools to either target the virus, boost immunity or protect cells from infection, also holds promise for future HIV cure strategies. In this Review, we discuss advances related to HIV cure in the last 5 years, highlight remaining knowledge gaps and identify priority areas for research for the next 5 years.
Publisher: Mary Ann Liebert Inc
Date: 04-2020
Publisher: Elsevier BV
Date: 06-2022
Publisher: American College of Physicians
Date: 02-09-2014
DOI: 10.7326/M14-1573
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: American Society for Microbiology
Date: 2007
DOI: 10.1128/CVI.00214-06
Abstract: Storage of high-quality cryopreserved peripheral blood mononuclear cells (PBMC) is often a requirement for multicenter clinical trials and requires a reproducibly high standard of practice. A quality assurance program (QAP) was established to assess an Australia-wide network of laboratories in the provision of high-quality PBMC (determined by yield, viability, and function), using blood taken from single donors (human immunodeficiency virus [HIV] positive and HIV negative) and shipped to each site for preparation and cryopreservation of PBMC. The aim of the QAP was to provide laboratory accreditation for participation in clinical trials and cohort studies which require preparation and cryopreservation of PBMC and to assist all laboratories to prepare PBMC with a viability of % and yield of % following thawing. Many laboratories failed to reach this standard on the initial QAP round. Interventions to improve performance included telephone interviews with the staff at each laboratory, two annual wet workshops, and direct access to a senior scientist to discuss performance following each QAP round. Performance improved substantially in the majority of sites that initially failed the QAP ( P = 0.002 and P = 0.001 for viability and yield, respectively). In a minority of laboratories, there was no improvement ( n = 2), while a high standard was retained at the laboratories that commenced with adequate performance ( n = 3). These findings demonstrate that simple interventions and monitoring of PBMC preparation and cryopreservation from multiple laboratories can significantly improve performance and contribute to maintenance of a network of laboratories accredited for quality PBMC fractionation and cryopreservation.
Publisher: Springer Science and Business Media LLC
Date: 07-11-2011
Abstract: Maraviroc (MVC) and other CCR5 antagonists are HIV-1 entry inhibitors that bind to- and alter the conformation of CCR5, such that CCR5 is no longer recognized by the viral gp120 envelope (Env) glycoproteins. Resistance to CCR5 antagonists results from HIV-1 Env acquiring the ability to utilize the drug-bound conformation of CCR5. Selecting for HIV-1 resistance to CCR5-antagonists in vitro is relatively difficult. However, the CCR5-using CC1/85 strain appears to be uniquely predisposed to acquiring resistance to several CCR5 antagonists in vitro including MVC, vicriviroc and AD101. Here, we show that Env derived from the parental CC1/85 strain is inherently capable of a low affinity interaction with MVC-bound CCR5. However, this phenotype was only revealed in 293-Affinofile cells and NP2-CD4/CCR5 cells that express very high levels of CCR5, and was masked in TZM-bl, JC53 and U87-CD4/CCR5 cells as well as PBMC, which express comparatively lower levels of CCR5 and which are more commonly used to detect resistance to CCR5 antagonists. Env derived from the CC1/85 strain of HIV-1 is inherently capable of a low-affinity interaction with MVC-bound CCR5, which helps explain the relative ease in which CC1/85 can acquire resistance to CCR5 antagonists in vitro . The detection of similar phenotypes in patients may identify those who could be at higher risk of virological failure on MVC.
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: Rockefeller University Press
Date: 06-09-1999
Abstract: The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed α1 circle) of T cell receptor rearrangement. By studying 532 normal in iduals, we found that α1 circle numbers in blood remain high for the first 10–15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control in iduals, α1 circle numbers in HIV-1–infected adults were significantly reduced however, there were many in iduals with normal α1 circle numbers. In 74 in iduals receiving highly active antiretroviral therapy, we found no appreciable effect on α1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in α1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as α1 circle numbers are normal in a substantial subset of HIV-1–infected in iduals.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2020
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/473925
Abstract: Despite the availability of effective combination antiretroviral therapy (cART), liver disease is one of the leading causes of morbidity and mortality in Human Immunodeficiency Virus (HIV)-infected in iduals, specifically, in the presence of viral hepatitis coinfection. HIV, a single stranded RNA virus, can bind to and activate both Toll-like receptor (TLR)7 and TLR8 in circulating blood mononuclear cells, but little is known about the effect of HIV on TLRs expressed in the liver. HIV can directly infect cells of the liver and HIV-mediated depletion of CD4+ T-cells in the gastrointestinal tract (GI tract) results in increased circulating lipopolysaccharide (LPS), both of which may impact on TLR signaling in the liver and subsequent liver disease progression. The potential direct and indirect effects of HIV on TLR signaling in the liver will be explored in this paper.
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S1386-6532(01)00195-0
Abstract: With decreased rates of HIV mortality and disease progression attributable to treatment with nucleoside analogue reverse transcriptase inhibitors (NRTIs), attention has now become focused on the toxicities of these forms of treatment. It is believed NRTIs cause a decrease in mitochondrial DNA (mtDNA) synthesis due to their inhibition of DNA polymerase gamma. This hypothesis is supported by in vitro data from muscle biopsies and human lymphoblastic cell lines. The resulting mitochondrial toxicity is thought to manifest itself in a variety of clinical symptoms including fatigue, fat wasting and peripheral neuropathy. A non-invasive test of mitochondrial toxicity is needed to assess toxicity and optimise HIV treatment strategies. Peripheral blood mononuclear cells (PBMC) and subcutaneous fat could be ideal and accessible sources of mtDNA for examining toxicity. The objectives of this study were (a) to develop an assay to quantify the mtDNA copy number of PBMC and obtain reproducible results and (b) to establish the utility of subcutaneous fat as a source of mtDNA for quantification. PBMC were isolated from blood by centrifugation over Ficoll-Paque and subcutaneous fat was obtained from two 3 mm punch skin biopsies. Following DNA extraction, the mtDNA copy number in each s le was quantified by real-time polymerase chain reaction (PCR). The real-time PCR assay was found to generate consistent and reproducible results with replicates of s les undertaken within the same run, and in two or more different runs, having a mean coefficient of variation of 11.3 and 17.2%, respectively. PBMC and subcutaneous fat contained 409+/-148 and 2042+/-391 copies of mtDNA per cell, respectively. From the work carried out it can be concluded that firstly, the real-time PCR assay generates consistent and reproducible results, and secondly that mtDNA can be extracted and quantified from PBMC and subcutaneous fat.
Publisher: Oxford University Press (OUP)
Date: 04-12-2019
Abstract: Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy. Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry. Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines. HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-06-2016
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/SH11110
Abstract: Age related morbidity among people living with HIV has increased as people with the virus live longer. This introduction provides an overview of all the articles which cover a spectrum of issues including particular diseases, the science of immunosenescence and the psycho-social challenges of ageing with HIV. It considers whether a syndrome of accelerated ageing exists among people with HIV finding that evidence is currently lacking to support this theory.
Publisher: Oxford University Press (OUP)
Date: 15-10-2013
DOI: 10.1093/CID/CIT476
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
Publisher: Future Medicine Ltd
Date: 04-2011
DOI: 10.2217/BMM.11.15
Abstract: Combination antiretroviral therapy (cART) has significantly reduced morbidity and mortality of HIV-infected patients, yet their life expectancy remains reduced compared with the general population. Most HIV-infected patients receiving cART have some persistent immune dysfunction characterized by chronic immune activation and premature aging of the immune system. Here we review biomarkers of T-cell activation (CD69, -25 and -38, HLA-DR, and soluble CD26 and -30) generalized immune activation (C-reactive protein, IL-6 and D-dimer) microbial translocation (lipopolysaccharide, 16S rDNA, lipopolysaccharide-binding protein and soluble CD14) and immune dysfunction of specific cellular subsets (T cells, natural killer cells and monocytes) in HIV-infected patients on cART and their relationship to adverse clinical outcomes including impaired CD4 T-cell recovery, as well as non-AIDS clinical events, such as cardiovascular disease.
Publisher: Oxford University Press (OUP)
Date: 15-07-2003
DOI: 10.1086/375850
Publisher: Springer Science and Business Media LLC
Date: 17-10-2018
Publisher: Springer Science and Business Media LLC
Date: 25-08-2015
DOI: 10.1038/MP.2015.111
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: Oxford University Press (OUP)
Date: 05-2017
Abstract: Discussion on the role of HIV infection and immune activation in liver resident monocytes.
Publisher: Wiley
Date: 19-05-2016
Abstract: Many treatment complications that occur late in childhood cancer survivors resemble age-related comorbidities observed in the elderly. An immune phenotype characterized by increased immune activation, systemic inflammation, and accumulation of late-differentiated memory CD57(+) CD28(-) T cells has been associated with comorbidities in the elderly. Here, we explored if this phenotype was present in young adult leukemia survivors following an average of 19 years from chemotherapy and/or radiotherapy completion, and compared this with that in age-matched controls. We found that markers of systemic inflammation-IL-6 and human C-reactive protein and immune activation-CD38 and HLA-DR on T cells, soluble CD (sCD)163 from monocytes and macrophages-were increased in survivors compared to controls. T-cell responses specific to cytomegalovirus (CMV) were also increased in survivors compared to controls while CMV IgG levels in survivors were comparable to levels measured in the elderly (>50years) and correlated with IL-6, human C-reactive protein, sCD163, and CD57(+) CD28(-) memory T cells. Immune activation and inflammation markers correlated poorly with prior chemotherapy and radiotherapy exposure. These data suggest that CMV infection/reactivation is strongly correlated with the immunological phenotype seen in young childhood leukemia survivors and these changes may be associated with the early onset of age-related comorbidities in this group.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-02-2015
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: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2011
Publisher: Elsevier BV
Date: 12-2019
Publisher: Springer Science and Business Media LLC
Date: 13-07-2021
DOI: 10.1038/S41467-021-24577-9
Abstract: The recent dramatic appearance of variants of concern of SARS-coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape from host immunity and antiviral therapeutics. Here, we employ genome-wide computational prediction and single-nucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved % silencing efficiency in virus-free models. Further, optimized and multiplexed Cas13b CRISPR RNAs (crRNAs) suppress viral replication in mammalian cells infected with replication-competent SARS-CoV-2, including the recently emerging dominant variant of concern B.1.1.7. The comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches does not impair the capacity of a potent single crRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 strains in infected mammalian cells, including the Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint for antiviral drug development to suppress and prevent a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.
Publisher: Oxford University Press (OUP)
Date: 15-03-2011
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 02-2011
Abstract: Amoebic encephalitis is an uncommon and usually fatal condition. This case describes successful treatment of a Balamuthia mandrillaris brain abscess using prolonged antimicrobial agents with complete excision. It illustrates the risk of dissemination from cutaneous to cerebral amoebic lesions, potential progression with corticosteroid therapy, and the prospect for curative excision.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.CLIM.2007.04.018
Abstract: Cytomegalovirus (CMV)-specific immunity was investigated in human immunodeficiency virus (HIV)-infected in iduals. A case-control (1:2) study was performed with cases defined as having a history of CMV end-organ disease (n=15) and controls (n=30) matched by current CD4(+) T cell count. CMV-specific CD8(+) T cells responses were quantified using the high throughput Quantiferon-CMV test (Cellestis, Melbourne, Australia). 40/44 (91%) had a positive Quantiferon-CMV test and the magnitude of response to CMV peptides correlated significantly with response to mitogen (p<0.0001) but not with CD4(+) T cell count at the time of testing, CD4(+) T cell nadir or HIV viral load. Cases had a significantly lower Quantiferon-CMV test than controls but there was no significant difference in response to mitogen or other antigens. In in iduals with a history of CMV disease, CMV-specific CD8(+) T cell responses are reduced even in the setting of CD4(+) T cell reconstitution.
Publisher: American Society of Hematology
Date: 07-2002
Abstract: Myasthenia gravis (MG) is the leading paraneoplastic manifestation of thymomas and is probably related to the capacity of thymomas to mature and export potentially autoreactive T cells. Why some thymomas are MG associated (MG+) and others are not (MG−) has been unclear. We addressed this question by comparing the percentages of intratumorous naive mature CD45RA+ thymocytes in 9 MG(+) and in 13 MG(−) thymomas by fluorescence-activated cell sorting analysis. Our results show that intratumorous naive CD4 T cells were present in all MG(+) thymomas and in one MG(−) thymoma with the development of MG only 2 months after surgery. By contrast, the percentage of naive CD4+ T cells was significantly reduced in all 13 MG(−) thymomas (P & .0001). Alterations in intratumorous thymopoiesis were reflected by corresponding alterations of naive T-cell subset composition in the blood, in that only MG(−) patients had significantly decreased levels (P = .02) of naive CD4+ T cells compared with age- and sex-matched control persons. We conclude that paraneoplastic MG is highly associated with the efficiency of thymomas to produce and export naive CD4+T cells. The acquisition of the CD45RA+ phenotype on CD4+ T cells during terminal intratumorous thymopoiesis is associated with the presence of MG in most thymoma patients.
Publisher: Oxford University Press (OUP)
Date: 24-10-2013
DOI: 10.1189/JLB.0713368
Abstract: Myeloid cells residing in the CNS and lymphoid tissues are targets for productive HIV-1 replication, and their infection contributes to the pathological manifestations of HIV-1 infection. The Envs can adopt altered configurations to overcome entry restrictions in macrophages via a more efficient and/or altered mechanism of engagement with cellular receptors. This review highlights evidence supporting an important role for macrophages in HIV-1 pathogenesis and persistence, which need to be considered for strategies aimed at achieving a functional or sterilizing cure. We also highlight that the molecular mechanisms underlying HIV-1 tropism for macrophages are complex, involving enhanced and/or altered interactions with CD4, CCR5, and/or CXCR4, and that the nature of these interactions may depend on the anatomical location of the virus.
Publisher: AMPCo
Date: 2012
DOI: 10.5694/MJA11.10809
Publisher: American Society for Microbiology
Date: 02-2000
DOI: 10.1128/JVI.74.3.1209-1223.2000
Abstract: Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) remain healthy though they harbor viral loads comparable to those in rhesus macaques that progress to AIDS. To assess the immunologic basis of disease resistance in mangabeys, we compared the effect of SIV infection on T-cell regeneration in both monkey species. Measurement of the proliferation marker Ki-67 by flow cytometry showed that mangabeys harbored proliferating T cells at a level of 3 to 4% in peripheral blood irrespective of their infection status. In contrast, rhesus macaques demonstrated a naturally high fraction of proliferating T cells (7%) that increased two- to threefold following SIV infection. Ki-67 + T cells were predominantly CD45RA − , indicating increased proliferation of memory cells in macaques. Quantitation of an episomal DNA product of T-cell receptor α rearrangement (termed α1 circle) showed that the concentration of recent thymic emigrants in blood decreased with age over a 2-log unit range in both monkey species, consistent with age-related thymic involution. SIV infection caused a limited decrease of α1 circle numbers in mangabeys as well as in macaques. Dilution of α1 circles by T-cell proliferation likely contributed to this decrease, since α1 circle numbers and Ki-67 + fractions correlated negatively. These findings are compatible with immune exhaustion mediated by abnormal T-cell proliferation, rather than with early thymic failure, in SIV-infected macaques. Normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2020
DOI: 10.1186/S12977-020-00532-2
Abstract: HIV-1 infects a wide range of CD4 + T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4 + T cell subsets and whether tropism changes during acute to chronic disease progression. HIV-1 envs were lified from the plasma of five C-HIV infected women from three untreated time points less than 2 months, 1-year and 3-years post-infection. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4 + T cell subset tropism was measured by flow cytometry. A total of 50 C-HIV envs were cloned and screened for functionality in pseudovirus infection assays. Phylogenetic and variable region characteristic analysis demonstrated evolution in envs between time points. We found 45 pseudoviruses were functional and all used CCR5 to mediate entry into NP2/CD4/CCR5 cells. In vitro infection assays showed transitional memory (TM) and effector memory (EM) CD4 + T cells were more frequently infected (median: 46% and 25% of total infected CD4 + T cells respectively) than naïve, stem cell memory, central memory and terminally differentiated cells. This was not due to these subsets contributing a higher proportion of the CD4 + T cell pool, rather these subsets were more susceptible to infection (median: 5.38% EM and 2.15% TM cells infected), consistent with heightened CCR5 expression on EM and TM cells. No inter- or intra-participant changes in CD4 + T cell subset tropism were observed across the three-time points. CD4 + T cell subsets that express more CCR5 were more susceptible to infection with C-HIV Envs, suggesting that these may be the major cellular targets during the first 3 years of infection. Moreover, we found that viral tropism for different CD4 + T cell subsets in vitro did not change between Envs cloned from acute to chronic disease stages. Finally, central memory, naïve and stem cell memory CD4 + T cell subsets were susceptible to infection, albeit inefficiently by Envs from all time-points, suggesting that direct infection of these cells may help establish the latent reservoir early in infection.
Publisher: Wiley
Date: 15-11-2011
DOI: 10.1038/ICB.2011.95
Abstract: Combination antiretroviral therapy (cART) has led to a very substantial reduction in morbidity and mortality in HIV-infected patients however, cART alone is unable to cure HIV and therapy is lifelong. Therefore, a new strategy to cure HIV is urgently needed. There is now a concerted effort from scientists, clinicians and funding agencies to identify ways to achieve either a functional cure (long-term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV-infected cells). Multiple strategies aiming at achieving a cure for HIV are currently being investigated, including both pharmacotherapy and gene therapy. In this review, we will review the rationale as well as in vitro and clinical trial data that support the role of histone deacetylase inhibitors as one approach to cure HIV.
Publisher: Elsevier BV
Date: 05-1993
DOI: 10.1016/0163-4453(93)95937-E
Abstract: Telehealth is an important tool in helping to provide services for hard-to-reach populations. One population that might benefit from telehealth are in iduals with fragile X syndrome (FXS). Although FXS is the leading inherited cause of intellectual disability, it is nonetheless a low incidence disorder. In iduals with FXS and their families are involved in research studies, clinical trials and receive interventions - many of which are only offered in a few locations in the United States and thus, not easily accessible to many families. The current project explored the feasibility of using telehealth procedures to collect multimodal behavioural and psychological assessment data from these families. Participation in the current study involved online surveys, measures of physiological indices of stress, live interviews and observations of mother-child interactions conducted via distance videoconferencing using the family's own technology when possible. Across all modes of data collection, we obtained information regarding the feasibility of participating entirely via distance by documenting missing data as well as each mother's overall impression of participating via distance. Our telehealth procedures were successfully implemented across a wide range of technology platforms with limited difficulty, and we documented little missing data due to technology-related challenges. Perhaps most importantly, however, our s le of mothers reported high satisfaction with participating via distance. These findings suggest that a wide range of services and types of assessments may be amenable to telehealth procedures. Further, the findings have immediate applications as the field shifts towards telehealth due to the coronavirus disease 2019 (COVID-19) pandemic.
Publisher: Public Library of Science (PLoS)
Date: 13-11-2014
Publisher: Springer Science and Business Media LLC
Date: 17-01-2012
DOI: 10.1007/S11904-011-0108-2
Abstract: Combination antiretroviral therapy (cART) has led to a reduction in morbidity and mortality in HIV-infected patients but therapy is lifelong and there is no cure for HIV. The major barriers to cure include HIV latency, which has been identified in different T-cell subsets, as well as persistence of HIV in anatomical reservoirs. We review recent developments in our understanding of the major reservoirs of HIV in patients on cART as well as how latency is established and maintained in T cells. Finally, we review the scientific rationale of and clinical experience with pharmacotherapeutic strategies aimed at eliminating latently infected cells.
Publisher: Elsevier BV
Date: 07-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
Publisher: Public Library of Science (PLoS)
Date: 28-02-2020
Publisher: Elsevier
Date: 2010
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 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: Springer Science and Business Media LLC
Date: 18-02-2019
DOI: 10.1038/S41467-019-08798-7
Abstract: HIV persists in latently infected CD4 + T cells during antiretroviral therapy (ART). Immune checkpoint molecules, including PD-1, are preferentially expressed at the surface of persistently infected cells. However, whether PD-1 plays a functional role in HIV latency and reservoir persistence remains unknown. Using CD4 + T cells from HIV-infected in iduals, we show that the engagement of PD-1 inhibits viral production at the transcriptional level and abrogates T-cell receptor (TCR)-induced HIV reactivation in latently infected cells. Conversely, PD-1 blockade with the monoclonal antibody pembrolizumab enhances HIV production in combination with the latency reversing agent bryostatin without increasing T cell activation. Our results suggest that the administration of immune checkpoint blockers to HIV-infected in iduals on ART may facilitate latency disruption.
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: Oxford University Press (OUP)
Date: 08-2013
Publisher: Elsevier BV
Date: 06-2023
Publisher: The American Association of Immunologists
Date: 2013
Abstract: The lineage relationships and fate of human dendritic cells (DCs) have significance for a number of diseases including HIV where both blood and tissue DCs may be infected. We used gene expression profiling of human monocyte and DC subpopulations sorted directly from blood and skin to define the lineage relationships. We also compared these with monocyte-derived DCs (MDDCs) and MUTZ3 Langerhans cells (LCs) to investigate their relevance as model skin DCs. Hierarchical clustering analysis showed that myeloid DCs clustered according to anatomical origin rather than putative lineage. Plasmacytoid DCs formed the most discrete cluster, but ex vivo myeloid cells formed separate clusters of cells both in blood and in skin. Separate and specific DC populations could be determined within skin, and the proportion of CD14+ dermal DCs (DDCs) was reduced and CD1a+ DDCs increased during culture, suggesting conversion to CD1a+-expressing cells in situ. This is consistent with origin of the CD1a+ DDCs from a local precursor rather than directly from circulating blood DCs or monocyte precursors. Consistent with their use as model skin DCs, the in vitro–derived MDDC and MUTZ3 LC populations grouped within the skin DC cluster. MDDCs clustered most closely to CD14+ DDCs furthermore, common unique patterns of C-type lectin receptor expression were identified between these two cell types. MUTZ3 LCs, however, did not cluster closely with ex vivo–derived LCs. We identified differential expression of novel genes in monocyte and DC subsets including genes related to DC surface receptors (including C-type lectin receptors, TLRs, and galectins).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-07-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-05-2008
Publisher: Wiley
Date: 04-1995
DOI: 10.1111/J.1445-5994.1995.TB02825.X
Abstract: Pulmonary disease is the most common reason for presentation and the major cause of death in HIV-infected patients. There has been an evolution in the optimal approach to the investigation of a pulmonary infiltrate in HIV-infected patients since the introduction of induced sputum for the diagnosis of Pneumocystis carinii pneumonia (PCP). To evaluate the usefulness of flexible fibreoptic bronchoscopy (FFB), bronchoalveolar lavage (BAL), transbronchial biopsy (TBB) and bronchial brushings (BB) in the diagnosis of pulmonary disease in HIV-infected patients and to examine the effect of FFB on changes in therapy and survival. The histories of all HIV-infected patients referred to Fairfield Hospital for FFB between January 1990 and June 1993 were examined retrospectively. Forty-two FFB were performed on 41 patients (40 male and one female). Definitive diagnoses made at FFB included Kaposi's sarcoma (KS) (n = 9), invasive aspergillosis (n = 5), PCP (n = 4), Mycobacterium avium complex (MAC) pneumonia (n = 2), cytomegalovirus (CMV) pneumonia (n = 1), Cryptococcus neoformans pneumonia (n = 1), microsporidium (n = 1) and Pseudomonas aeruginosa pneumonia (n = 1). TBB and BB did not provide a diagnosis for diseases not seen macroscopically at FFB or diagnosed by BAL. FFB findings altered diagnosis in 21/42 (50%) presentations and changed therapy in 26/42 (62%) cases. FFB together with BAL altered the working diagnosis and changed therapy in a significant number of patients. TBB and BB should not be routinely performed in all patients as these procedures are of limited value in this setting.
Publisher: Springer Science and Business Media LLC
Date: 24-09-2018
DOI: 10.1038/S41598-018-32585-X
Abstract: We explored the gut microbiota profile among HIV-infected in iduals with erse immune recovery profiles following long-term suppressive ART and investigated the relationship between the altered bacteria with markers of immune dysfunction. The microbiota profile of rectal swabs from 26 HIV-infected in iduals and 20 HIV-uninfected controls were examined. Patients were classified as suboptimal responders, sIR (n = 10, CD4 T-cell cells/ul) and optimal responders, oIR (n = 16, CD4 T-cell cells/ul) after a minimum of 2 years on suppressive ART. Canonical correlation analysis(CCA) and multiple regression modelling were used to explore the association between fecal bacterial taxa abundance and immunological profiles in optimal and suboptimal responders. We found Fusobacterium was significantly enriched among the HIV-infected and the sIR group. CCA results showed that Fusobacterium abundance was negatively correlated with CD4 T-cell counts, but positively correlated with CD4 T-cell activation and CD4 Tregs. Multiple linear regression analysis adjusted for age, baseline CD4 T-cell count, antibiotic exposure and MSM status indicated that higher Fusobacterium relative abundance was independently associated with poorer CD4 T-cell recovery following ART. Enrichment of Fusobacterium was associated with reduced immune recovery and persistent immune dysfunction following ART. Modulating the abundance of this bacterial taxa in the gut may be a viable intervention to improve immune reconstitution in our setting.
Publisher: Springer Science and Business Media LLC
Date: 03-2016
DOI: 10.1038/NBT.3502
Publisher: Public Library of Science (PLoS)
Date: 24-08-2018
Publisher: Springer Science and Business Media LLC
Date: 20-07-2012
DOI: 10.1038/NRI3262
Publisher: SAGE Publications
Date: 11-2010
Abstract: The aims of the study were to assess whether Treponema pallidum-specific IgM may provide a useful marker of infectious syphilis in human immunodeficiency virus (HIV)-infected patients, and to compare the performance of a prototype IgM-rapid point-of-care test (PoCT) with a standard IgM-enzyme immunoassay (EIA). Twenty s les from HIV-infected patients with untreated syphilis ( n = 4 primary syphilis, n = 11 secondary and n = 5 early latent) and 51 follow-up s les at three, six or 12 months after treatment were tested for the presence of IgM with the Mercia-EIA (Microgen Bioproducts Ltd, Camberley, UK) and a prototype PoCT (Select Vaccines Ltd, Melbourne, Australia). Although s le numbers were small, IgM detection by EIA appears to be a reliable marker for untreated syphilis in HIV-infected patients with primary (4/4 IgM-positive) or secondary syphilis (10/11 IgM-positive, 1/11 equivocal). After treatment, IgM was no longer detected after three months in the majority of patients (87%) and was either negative or equivocal in all patients after six and 12 months. The overall sensitivity of the IgM-PoCT was 82% and varied with clinical stage, being highest in secondary (10/10 EIA positives) but lower in primary (2/4 EIA positives) and early latent syphilis (2/3 EIA positives). Overall specificity was 95%. Rapid detection of IgM would enable clinicians to distinguish between past-treated and infectious syphilis and allow for diagnosis and treatment in a single visit.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
DOI: 10.1038/NM.4108
Publisher: American Society for Microbiology
Date: 05-2011
DOI: 10.1128/JVI.00106-11
Abstract: Maraviroc (MVC) inhibits the entry of human immunodeficiency virus type 1 (HIV-1) by binding to and modifying the conformation of the CCR5 extracellular loops (ECLs). Resistance to MVC results from alterations in the HIV-1 gp120 envelope glycoproteins (Env) enabling recognition of the drug-bound conformation of CCR5. To better understand the mechanisms underlying MVC resistance, we characterized the virus-cell interactions of gp120 from in vitro -generated MVC-resistant HIV-1 (MVC-Res Env), comparing them with those of gp120 from the sensitive parental virus (MVC-Sens Env). In the absence of the drug, MVC-Res Env maintains a highly efficient interaction with CCR5, similar to that of MVC-Sens Env, and displays a relatively modest increase in dependence on the CCR5 N terminus. However, in the presence of the drug, MVC-Res Env interacts much less efficiently with CCR5 and becomes critically dependent on the CCR5 N terminus and on positively charged elements of the drug-modified CCR5 ECL1 and ECL2 regions (His88 and His181, respectively). Structural analysis suggests that the Val323 resistance mutation in the gp120 V3 loop alters the secondary structure of the V3 loop and the buried surface area of the V3 loop–CCR5 N terminus interface. This altered mechanism of gp120-CCR5 engagement dramatically attenuates the entry of HIV-1 into monocyte-derived macrophages (MDM), cell-cell fusion activity in MDM, and viral replication capacity in MDM. In addition to confirming that HIV-1 escapes MVC by becoming heavily dependent on the CCR5 N terminus, our results reveal novel interactions with the drug-modified ECLs that are critical for the utilization of CCR5 by MVC-Res Env and provide additional insights into virus-cell interactions that modulate macrophage tropism.
Publisher: Mary Ann Liebert Inc
Date: 12-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2011
Publisher: Mary Ann Liebert Inc
Date: 02-2006
Abstract: The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was ided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2018
Publisher: Informa UK Limited
Date: 04-2004
Publisher: Public Library of Science (PLoS)
Date: 09-04-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
DOI: 10.1097/01.AIDS.0000131384.53350.59
Abstract: We describe here a severe flare of hepatitis caused by lamivudine-resistant hepatitis B virus(HBV) in an HIV/HBV co-infected in idual.Lamivudine-resistant HBV was detected 6 months before the development of severe hepatitis. Sequencing of the HBV genome isolated from the patients' serum did not identify compensatory mutations in the HBV polymerase that may have restored viral replication. However, a strong HBV-specific CD8 T-cell response was identified and may have resulted in the severe hepatitis.
Publisher: Elsevier BV
Date: 2022
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: Elsevier BV
Date: 05-2020
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 28-11-2007
Abstract: Hepatitis B virus (HBV) infection is a non-cytopathic hepatotropic virus that can lead to severe liver disease including acute hepatitis, cirrhosis and hepatocellular carcinoma. Successful clearance of the virus as well as the establishment of liver disease is largely driven by a complex interaction between the virus and the host immune response. In this review, the immunological events, including both the innate and adaptive immune response are discussed in the setting of both acute and chronic HBV infection and liver disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2015
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/S41467-017-00057-X
Abstract: The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.
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: Rockefeller University Press
Date: 15-03-1999
Abstract: To determine the role of CD8+ T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8+ T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2013
Publisher: Springer Science and Business Media LLC
Date: 09-03-2012
Abstract: Hepatic Flare (HF) after initiation of highly active antiretroviral therapy (HAART) in HIV-HBV coinfected in iduals is well recognized but prospective data on predictors and subsequent outcome are limited. The Tenofovir in HIV-HBV coinfection study was a randomized clinical trial of HBV-active HAART including lamivudine and/or tenofovir in antiretroviral naïve HIV-HBV in iduals in Thailand. Early HF (EHF) was defined as ALT 5 × ULN during the first 12 weeks. EHF was observed in 8 (22%) of in iduals at a median of 56 days. 6/8 EHF cases were asymptomatic and resolved with HAART continuation, however one subject with underlying cirrhosis died following rapid hepatic decompensation. EHF was significantly associated with higher baseline ALT (79 IU/L vs 36 IU/L non-EHF, p = 0.008) and HBV DNA (9.9 log 10 c/ml vs 8.4 log 10 c/ml non EHF, p = 0.009), and subsequent serological change. HBeAg loss occurred in 75% of EHF cases versus 22% in non-EHF ( p = 0.04), and HBsAg loss in 25% of EHF cases versus 4% of non-EHF ( p = 0.053). EHF after HBV active HAART initiation was frequently observed in this population. Timing of EHF, association with elevated ALT and HBV DNA and high rate of seroconversion are all consistent with immune restoration as the likely underlying process. NCT00192595 .
Publisher: Oxford University Press (OUP)
Date: 17-10-2011
Abstract: Most patients with human immunodeficiency virus (HIV) who remain CD4(+) T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4(+) T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-α), we examined these factors in HIV patients with good or poor CD4(+) T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4(+) T cells of patients with poor CD4(+) T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4(+) T-cell recovery was also associated with CD4(+) T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4(+) T-cell recovery may be adversely affected by the effects of IFN-α, which may be amenable to therapeutic intervention.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-01-2022
DOI: 10.1126/SCITRANSLMED.ABL3836
Abstract: In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4 + T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti–PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4 + T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4 + T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti–PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti–PD-1 with other interventions to reduce the HIV reservoir.
Publisher: Oxford University Press (OUP)
Date: 29-10-2018
Abstract: Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.
Publisher: Springer Science and Business Media LLC
Date: 04-01-2016
DOI: 10.1007/S13365-015-0413-4
Abstract: Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.
Publisher: Wiley
Date: 09-08-2022
DOI: 10.1002/ANA.26456
Abstract: Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure and possible cause of comorbid disease. However, the size and replication competent nature of the central nervous system (CNS) reservoir is unclear. Here, we used the intact proviral DNA assay (IPDA) to provide the first quantitative assessment of the intact and defective HIV reservoir in the brain of people with HIV (PWH). Total, intact, and defective HIV proviruses were measured in autopsy frontal lobe tissue from viremic (n = 18) or virologically suppressed (n = 12) PWH. Total or intact/defective proviruses were measured by detection of HIV pol or the IPDA, respectively, through use of droplet digital polymerase chain reaction (ddPCR). HIV‐seronegative in iduals were included as controls (n = 6). Total HIV DNA was present at similar levels in brain tissues from untreated viremic and antiretroviral (ART)‐suppressed in iduals (median = 22.3 vs 26.2 HIV pol copies/10 6 cells), reflecting a stable CNS reservoir of HIV that persists despite therapy. Furthermore, 8 of 10 viremic and 6 of 9 virally suppressed PWH also harbored intact proviruses in the CNS (4.63 vs 12.7 intact copies/10 6 cells). Viral reservoirs in CNS and matched lymphoid tissue were similar in the composition of intact and/or defective proviruses, albeit at lower levels in the brain. Importantly, CNS resident CD68+ myeloid cells in virally suppressed in iduals harbored HIV DNA, directly showing the presence of a CNS resident HIV reservoir. Our results demonstrate the first evidence for an intact, potentially replication competent HIV reservoir in the CNS of virally suppressed PWH. ANN NEUROL 2022 :532–544
Publisher: Springer Science and Business Media LLC
Date: 05-03-2016
Publisher: Mary Ann Liebert Inc
Date: 07-1996
Abstract: The CD4 glycoprotein is the major cellular receptor for HIV. CD4 surface expression of monocytes decreases with time in culture while their susceptibility to HIV-1 increases. Our aim was to investigate whether this phenomenon occurs in macrophages that have differentiated in vivo by investigating CD4 expression and HIV-1 infection of human alveolar macrophages (AMs). Using flow cytometry to detect CD4 expression by Leu-3a labeled indirectly with fluorescein isothiocyanate or allophycocyanin, we found that CD4 was expressed at low but detectable levels, despite the high background autofluorescence well described in AMs. This finding was supported by the detection of CD4 mRNA in AMs using RT-PCR. T cell contamination of mRNA extracts of AMs was excluded by lifying in parallel with primers to the constant region of the T cell receptor. Despite this low level of surface CD4, recombinant soluble CD4 and anti-CD4 antibody completely inhibited HIV-1 infection of AMs. We conclude that CD4, although expressed at low levels on the surface of AMs, appears to be critical to HIV-1 infection of these cells.
Publisher: Georg Thieme Verlag KG
Date: 05-2006
Abstract: Hepatitis B virus (HBV) infection in immunocompetent adults usually results in a self-limited, transient liver disease and viral clearance, with only a small percentage (5 to 10%) developing chronic hepatitis associated with viral persistence. In contrast, when neonates are infected, more than 90% become persistently infected, suffering differing degrees of chronic liver disease. Activation of immunity plays a central role in host-virus interactions, greatly influencing viral replication and the clinical outcome of infection. Although all of the specific mechanisms and consequences of this interaction have not been elucidated, the purpose of this article is to describe the basic arms of the immune system as they interact with the HBV and describe the present state of knowledge in this area. These arms may be ided broadly into innate and specific immune responses, and they have different roles and responses in acute and chronic infection.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2001
Abstract: We used a new real-time polymerase chain reaction (PCR)-based assay that is sensitive, has a wide dynamic linear range, and is highly reproducible to quantify hepatitis B virus (HBV) DNA in the serum of infected in iduals undergoing potent antiviral therapy. In addition, we made frequent measurements of viral load after initiation of treatment and maintained follow-up to about 12 weeks. To analyze the data we used a new model of HBV decay, which takes into account that existing drug treatments do not completely block de novo infection and the possibility of noncytolytic loss of infected cells. On initiation of therapy, there was a mean delay of 1.6 days followed by a biphasic or muliphasic decay of plasma HBV DNA. The slope of the first phase varied considerably, with one in idual having rapid decay, corresponding to a virion half-life of 1 hour, but others showing half-lives of up to 92 hours. In iduals either had a slow second-phase decline (t((1/2)) = 7.2 +/- 1.2 days) or a flat second phase. Some in iduals exhibited a complex "staircase pattern" of decay, with further phases of viral DNA decline and phases with little change in viral load.
Publisher: The American Association of Immunologists
Date: 08-2019
Abstract: CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.
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: 24-08-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-11-2009
DOI: 10.1002/HEP.22754
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-09-2016
Publisher: Future Medicine Ltd
Date: 07-2009
DOI: 10.2217/HIV.09.19
Abstract: Liver disease is a major cause of mortality in in iduals with HIV–HBV coinfection. The pathogenesis of liver disease in this setting is unknown, but is likely to involve drug toxicity, infection of hepatic cells with both HIV and HBV, and an altered immune response to HBV. The availability of therapeutic agents that target both HIV and HBV replication enable dual viral suppression, and assessment of chronic hepatitis B is important prior to commencement of antiretroviral therapy. Greater importance is now placed on HBV DNA levels and staging of liver fibrosis, either by liver biopsy or noninvasive measurement, such as transient elastography, since significant liver fibrosis may exist in the presence of normal liver function tests. Earlier treatment of both HIV and HBV is now generally advocated and treatment is usually lifelong.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2008
DOI: 10.2174/157016208784324967
Abstract: DG17 is an orally available prodrug of DG35 (a novel HIV protease inhibitor with variable pharmacokinetics). These studies aimed to optimize DG17 pharmacokinetics by gastric acid neutralization and ritonavir pharmacoenhancement. Both studies were conducted using a randomized, cross-over design in which 6 healthy in iduals were administered a single dose of 100mg or 200mg DG17, half with the study intervention (sodium bicarbonate solution in the first study, low dose ritonavir in the second). After a one week washout period, each subject was then administered a second dose of DG17, with the study intervention only administered to the other half. Cmax and AUC increases with gastric acid neutralization were greatest in those with the lowest absorption of DG17 alone. All doses were subsequently given with sodium bicarbonate solution in the second study. Low-dose ritonavir co-administration with DG17 increased DG35 C(max) (median 1437 versus 100 ng/ml, p=0.028) and AUC (median 6975 versus 154ng/ml*hr, p=0.028) compared with DG17 without ritonavir. Plasma DG35 exceeded the IC(90) for HIV for > or = 12 hours following a single DG17/ritonavir dose. No significant adverse events occurred. Single dose DG17 is safe and best administered in a manner preventing gastric acid degradation and with low-dose ritonavir.
Publisher: Wiley
Date: 09-10-2018
DOI: 10.1002/CPT.1220
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: 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: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2018
Publisher: Elsevier BV
Date: 10-2004
Publisher: Oxford University Press (OUP)
Date: 18-01-2013
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S1386-6532(02)00111-7
Abstract: Despite the considerable successes of highly active antiretroviral therapy, new classes of therapeutic agents are still urgently needed. Unfortunately, the emergence of antiviral resistance and drug toxicity remain challenging obstacles to successful treatment in many HIV-1-infected in iduals. HIV-1 entry is a multi-step process that is an attractive target for the development of new classes of therapeutic agents. Considerable progress has been made in the understanding of HIV-1 cell entry, enabling the design of specific agents that can inhibit each step of cellular entry. A number of promising agents have commenced clinical trials, including the attachment inhibitor PRO 542, co-receptor inhibitor AMD3100 and fusion inhibitor T-20. A greater number of HIV-1 entry inhibitors are in preclinical development. This review outlines the mechanisms involved in HIV-1 entry and the sites of action of specific HIV-1 inhibitors.
Publisher: Oxford University Press (OUP)
Date: 12-06-2013
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: 26-12-2013
Publisher: Public Library of Science (PLoS)
Date: 28-09-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
Publisher: Public Library of Science (PLoS)
Date: 06-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
Publisher: Public Library of Science (PLoS)
Date: 02-07-2015
Publisher: Elsevier BV
Date: 07-2013
Publisher: Wiley
Date: 10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 19-11-2020
DOI: 10.1101/2020.11.18.389312
Abstract: Mutation-driven evolution of SARS coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape routes from host immunity and antiviral therapeutics. Here, we employed genome-wide computational prediction and singlenucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved % silencing efficiency in virus free-models. Further, optimized and multiplexed gRNAs suppressed viral replication by up to 90% in mammalian cells infected with replication-competent SARS-CoV-2. Unexpectedly, the comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches do not impair the capacity of a potent single gRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 in infected mammalian cells, including the highly infectious and globally disseminated Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint of antiviral therapeutics to simultaneously suppress a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2016
DOI: 10.1038/NRI.2016.19
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2018
Publisher: American Chemical Society (ACS)
Date: 18-02-2021
Publisher: Springer Science and Business Media LLC
Date: 30-08-2022
Publisher: Dustri-Verlgag Dr. Karl Feistle
Date: 11-2015
DOI: 10.5414/CP202386
Publisher: Elsevier BV
Date: 09-2014
Publisher: AMPCo
Date: 04-2017
DOI: 10.5694/MJA16.01451
Publisher: Elsevier BV
Date: 09-2002
DOI: 10.1016/S0166-3542(02)00071-2
Abstract: Hepatitis B virus (HBV) causes a generally non-cytopathic infection in the liver. Even though HBV is a DNA virus, it replicates via reverse transcription which is coordinated within the viral nucleocapsid by the virus-specific polymerase. The major transcriptional template is the viral mimichromosome from which the viral DNA exists as a covalently closed circular (ccc) molcule. The virus infects hepatocytes but can also be found in non-hepatocyte reservoirs such as bile-duct epithelium, mesangial cells of the kidney, pancreatic islet cells and lymphoid cells. When patients infected with HBV are treated with either interferon alpha or lamivudine, responses are variable and unpredictable. Sophisticated mathematical models analysing the dynamics of viral clearance during antiviral therapy have recently been applied to chronic hepatitis B. Typically complex profiles, rather than the usual biphasic responses seen with other diseases have been observed, indicating that antiviral efficacy requires substantila improvement. This may be achieved with combination chemotherapy. However, chronic hepatitis B is a complex and heterogeneous disease entity, and the challenge for the future is to define measurable end-points of treatment and address key virological issues such as the role of cccDNA and extra-hepatocyte replication in treatment failure. Clearly, new therapies and effective combination therapy protocols are urgently required in order to improve the present poor response rates in patients undergoing treatment.
Publisher: Wiley
Date: 12-08-2023
DOI: 10.1002/ANA.26750
Abstract: Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023
Publisher: Elsevier BV
Date: 10-2022
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: American Society for Microbiology
Date: 10-2011
DOI: 10.1128/JCM.01018-11
Abstract: We developed a real-time PCR to quantify 16S rRNA gene levels in plasma from HIV-infected patients as a marker of microbial translocation. The assay uses shrimp nuclease (SNuc) to eliminate DNA contamination, giving high sensitivity and low variability. The 16S rRNA gene levels measured in plasma from HIV patients correlated significantly with lipopolysaccharide levels.
Publisher: American Society for Microbiology
Date: 15-03-2010
DOI: 10.1128/JVI.02124-09
Abstract: Following treatment of hepatitis B virus (HBV) monoinfection, HBV-specific T-cell responses increase significantly however, little is known about the recovery of HBV-specific T-cell responses following HBV-active highly active antiretroviral therapy (HAART) in HIV-HBV coinfected patients. HIV-HBV coinfected patients who were treatment naïve and initiating HBV-active HAART were recruited as part of a prospective cohort study in Thailand and followed for 48 weeks ( n = 24). Production of gamma interferon (IFN-γ) and tumor necrosis factor α (TNF-α) in both HBV- and HIV-specific CD8 + T cells was quantified using intracellular cytokine staining on whole blood. Following HBV-active HAART, the median (interquartile range) log decline from week 0 to week 48 for HBV DNA was 5.8 log (range, 3.4 to 6.7) IU/ml, and for HIV RNA it was 3.1 (range, 2.9 to 3.5) log copies/ml ( P 0.001 for both). The frequency of HIV Gag-specific CD8 + T-cell responses significantly decreased (IFN-γ, P 0.001 TNF-α, P = 0.05). In contrast, there was no significant change in the frequency (IFN-γ, P = 0.21 TNF-α, P = 0.61 and IFN-γ and TNF-α, P = 0.11) or magnitude (IFN-γ, P = 0.13 TNF-α, P = 0.13 and IFN-γ and TNF-α, P = 0.13) of HBV-specific CD8 + T-cell responses over 48 weeks of HBV-active HAART. Of the 14 in iduals who were HBV e antigen (HBeAg) positive, 5/14 (36%) lost HBeAg during the 48 weeks of follow-up. HBV-specific CD8 + T cells were detected in 4/5 (80%) of patients prior to HBeAg loss. Results from this study show no sustained change in the HBV-specific CD8 + T-cell response following HBV-active HAART. These findings may have implications for the duration of treatment of HBV in HIV-HBV coinfected patients, particularly in HBeAg-positive disease.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2019
DOI: 10.1038/S41577-018-0085-4
Abstract: A variety of interventions to induce a functional cure of HIV are being explored, with the aim being to allow patients to cease antiretroviral therapy (ART) for prolonged periods of time or for life. These interventions share the goal of inducing ART-free remission from HIV pathogenesis and disease progression but achieve this in quite different ways, by reducing the size of the latent reservoir (for ex le, small-molecule stimulation of latently infected cells), reducing the number of target cells available for the virus (for ex le, gene therapy) or improving immune responses (for ex le, active or passive immunotherapy). Here, we consider a number of these alternative strategies for inducing post-treatment control of HIV and use mathematical modelling to predict the scale of the challenge inherent in these different approaches. For many approaches, over 99.9% efficacy will likely be required to induce durable ART-free remissions. The efficacy of in idual approaches is currently far below what we predict will be necessary, and new technologies to achieve lifelong functional cure are needed.
Publisher: Informa UK Limited
Date: 10-2009
DOI: 10.1080/09540120902803166
Abstract: This paper explores HIV-infected women's experiences of considering and using recommended interventions during pregnancy and postpartum to reduce mother-to-child transmission of HIV. Data were collected from 45 HIV-infected women aged 18-44 years living in Melbourne, Australia. A semi-structured interview was used to collect qualitative information on women's reproductive experience and intentions. The 15 women who had their children after their HIV diagnosis engaged in significant work including surveillance and safety work to minimise stigma and infection, information work to inform decisions and actions, accounting work to calculate risk and benefit, hope and worry work concerning a child's infection status and impact of interventions, work to redefine an acceptable maternal identity, work to prepare an alternative story to counter the disclosure effect of the intervention and emotional work to reconcile guilt when considering these interventions. This study provides a framework to help clinicians understand the real and on-going "work" that women engage in when they are considering interventions recommended by their physicians to reduce transmission of HIV. Even in circumstances where access to and acceptance of interventions are high, women continue to engage in this work even after they have a made a decision about a particular intervention.
Publisher: American Society for Microbiology
Date: 2007
DOI: 10.1128/JCM.01830-06
Publisher: American Chemical Society (ACS)
Date: 11-04-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00462
Abstract: The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class. Here, we describe the optimization of the hit class, defining the functionality necessary for HIV gene activation and for improving in vitro metabolism and solubility. The optimized compounds displayed enhanced HIV gene expression in HEK293 and Jurkat 10.6 latency cellular models and increased unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected in iduals on ART, demonstrating the potential of the 2-acylaminothiazole class as latency-reversing agents.
Publisher: Oxford University Press (OUP)
Date: 15-08-2004
DOI: 10.1086/422602
Publisher: AMPCo
Date: 11-2016
DOI: 10.5694/MJA16.00934
Abstract: Criminal cases involving human immunodeficiency virus transmission or exposure require that courts correctly comprehend the rapidly evolving science of HIV transmission and the impact of an HIV diagnosis. This consensus statement, written by leading HIV clinicians and scientists, provides current scientific evidence to facilitate just outcomes in Australian criminal cases involving HIV.Main recommendations: Caution should be exercised when considering charges or prosecutions regarding HIV transmission or exposure because:Scientific evidence shows that the risk of HIV transmission during sex between partners of different HIV serostatus can be low, negligible or too low to quantify, even when the HIV-positive partner is not taking effective antiretroviral therapy, depending on the nature of the sexual act, the viral load of the partner with HIV, and whether a condom or pre-exposure prophylaxis is employed to reduce risk.The use of phylogenetic analysis in cases of suspected HIV transmission requires careful consideration of its limited probative value as evidence of causation of HIV infection, although such an approach may provide valuable information, particularly in relation to excluding HIV transmission between in iduals.Most people recently infected with HIV are able to commence simple treatment providing them a normal and healthy life expectancy, largely comparable with their HIV-negative peers. Among people who have been diagnosed and are receiving treatment, HIV is rarely life threatening. People with HIV can conceive children with negligible risk to their partner and low risk to their child.Changes in management as result of the consensus statement: Given the limited risk of HIV transmission per sexual act and the limited long term harms experienced by most people recently diagnosed with HIV, appropriate care should be taken before HIV prosecutions are pursued. Careful attention should be paid to the best scientific evidence on HIV risk and harms, with consideration given to alternatives to prosecution, including public health management.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1093/OFID/OFW035
Abstract: Background. Advanced fibrosis occurs more commonly in human immunodeficiency virus (HIV)-hepatitis B virus (HBV) coinfected in iduals therefore, fibrosis monitoring is important in this population. However, transient elastography (TE) data in HIV-HBV coinfection are lacking. We aimed to assess liver fibrosis using TE in a cross-sectional study of HIV-HBV coinfected in iduals receiving combination HBV-active (lamivudine and/or tenofovir/tenofovir-emtricitabine) antiretroviral therapy, identify factors associated with advanced fibrosis, and examine change in fibrosis in those with & TE assessment. Methods. We assessed liver fibrosis in 70 HIV-HBV coinfected in iduals on HBV-active combination antiretroviral therapy (cART). Change in fibrosis over time was examined in a subset with more than 1 TE result (n = 49). Clinical and laboratory variables at the time of the first TE were collected, and associations with advanced fibrosis (≥F3, Metavir scoring system) and fibrosis regression (of least 1 stage) were examined. Results. The majority of the cohort (64%) had mild to moderate fibrosis at the time of the first TE, and we identified alanine transaminase, platelets, and detectable HIV ribonucleic acid as associated with advanced liver fibrosis. Alanine transaminase and platelets remained independently advanced in multivariate modeling. More than 28% of those with & TE subsequently showed liver fibrosis regression, and higher baseline HBV deoxyribonucleic acid was associated with regression. Prevalence of advanced fibrosis (≥F3) decreased 12.3% (32.7%–20.4%) over a median of 31 months. Conclusions. The observed fibrosis regression in this group supports the beneficial effects of cART on liver stiffness. It would be important to study a larger group of in iduals with more advanced fibrosis to more definitively assess factors associated with liver fibrosis regression.
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: Springer Science and Business Media LLC
Date: 15-07-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2001
Publisher: Public Library of Science (PLoS)
Date: 10-03-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-06-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2009
Publisher: Public Library of Science (PLoS)
Date: 08-09-2020
Publisher: Public Library of Science (PLoS)
Date: 23-10-2015
Publisher: Springer Science and Business Media LLC
Date: 11-07-2013
Abstract: Recent cases of successful control of human immunodeficiency virus (HIV) by bone marrow transplant in combination with suppressive antiretroviral therapy (ART) and very early initiation of ART have provided proof of concept that HIV infection might now be cured. Current efforts focusing on gene therapy, boosting HIV-specific immunity, reducing inflammation and activation of latency have all been the subject of recent excellent reviews. We now propose an additional avenue of research towards a cure for HIV: targeting HIV apoptosis regulatory pathways. The central enigma of HIV disease is that HIV infection kills most of the CD4 T cells that it infects, but those cells that are spared subsequently become a latent reservoir for HIV against which current medications are ineffective. We propose that if strategies could be devised which would favor the death of all cells which HIV infects, or if all latently infected cells that release HIV would succumb to viral-induced cytotoxicity, then these approaches combined with effective ART to prevent spreading infection, would together result in a cure for HIV. This premise is supported by observations in other viral systems where the relationship between productive infection, apoptosis resistance, and the development of latency or persistence has been established. Therefore we propose that research focused at understanding the mechanisms by which HIV induces apoptosis of infected cells, and ways that some cells escape the pro-apoptotic effects of productive HIV infection are critical to devising novel and rational approaches to cure HIV infection.
Publisher: Springer London
Date: 2014
Publisher: Mary Ann Liebert Inc
Date: 07-2018
Publisher: Public Library of Science (PLoS)
Date: 04-08-2011
Publisher: Mary Ann Liebert Inc
Date: 03-2014
Publisher: Mary Ann Liebert Inc
Date: 02-2004
DOI: 10.1089/088922204773004879
Abstract: A patient with HIV infection who experienced immune reconstitution after highly active antiretroviral therapy (HAART) [increase in CD4 T cell count from 600/microl] presented with severe Graves' disease 32 months after commencing HAART. A comprehensive clinical and laboratory study demonstrated pronounced regional lymphadenopathy and thymic enlargement at presentation, and that the onset of thyrotropin receptor antibody production was associated with increased production of soluble CD30 (a marker of type 2 immune responses). Blood naive CD8 T cell counts and TREC levels in both CD4 and CD8 T cells were increased at multiple time points compared with carefully selected controls. We conclude that the Graves' disease in this patient was associated with abnormally high blood counts of thymus-derived T cells, and propose that Graves' disease after HAART in this and other HIV patients may result from failure to delete autoreactive T cell clones in the regenerating thymus.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 07-2002
Abstract: The introduction of lamivudine (LMV) for the treatment of chronic hepatitis B infection has been an important advance in the management of this disease. However, the long-term efficacy of LMV may become limited by the emergence of antiviral-resistant hepatitis B virus (HBV) mutants. The two most common LMV-resistant mutants produce changes in the viral polymerase protein (rt) of rtM204I and rtL180M/M204V (previously rtM550I and rtL526M/M550V). A number of studies have demonstrated that these HBV mutants appear to be replication impaired, both in vitro and in vivo. The detection and selection of compensatory mutations in the polymerase protein that restore the replication phenotype of these HBV mutants have been poorly described to date. The effects of mutations in the fingers subdomain of the viral polymerase protein arising as a consequence of vaccine and hepatitis B immune globulin (HBIg) selected changes in the overlapping envelope gene (S), and a determinant of the hepatitis Bs antigen (HBsAg) were analyzed in vitro. The LMV-resistant HBV mutants rtM204I and rtL180M/M204V produced substantially weaker HBV DNA replicative intermediate signals by Southern blot analysis and less total intracellular HBV DNA by real-time PCR compared to wild-type virus. The viral polymerase protein of these mutants produced little detectable radiolabeled HBV DNA in an endogenous polymerase assay. In contrast, the HBV a determinant HBIg/vaccine escape mutants sP120T, sT123N, sG145R, and sD144E/G145R (that produce rtT128N, Q130P, rtW153Q, and rtG153E respectively) yielded as much virus as wild-type HBV while the sM133L (rtY141S) mutant was replication impaired. Two of these mutants, rtT128N and rtW153Q, when introduced into a replication-competent HBV vector containing the rtL180M/M204V polymerase mutation restored the replication phenotype of this LMV-resistant mutant. These viruses produced levels of intracellular HBV DNA as determined by Southern blot and real-time PCR that were comparable to those of wild-type HBV, indicating that the changes in the fingers subdomain were able to compensate for the reduced replication of the LMV-resistant mutations. Since these viruses carry mutations in the a determinant of HBsAg that may potentially decrease the ability of anti-HBs antibody to neutralize these viruses, these HBV mutants also have the potential to behave as vaccine escape mutants.
Publisher: Elsevier BV
Date: 2018
Publisher: Public Library of Science (PLoS)
Date: 02-08-2016
Publisher: CSIRO Publishing
Date: 2008
DOI: 10.1071/SH07041
Abstract: Objectives: To determine the upper limit for the incidence of clinically important HIV superinfection among HIV-infected men who have sex with men (MSM) and its relationship with engagement in unsafe sexual practices. Methods: This was a retrospective cohort and nested case-control study. Electronic files of all HIV-infected MSM not on antiretroviral therapy were reviewed. Those clients with sudden, unexplained and sustained declines in CD4 T-cell counts and increases in plasma HIV RNA were considered as being putatively superinfected with HIV and were recruited as cases, whereas those without these features were recruited as controls (four per case) to answer a self-administered questionnaire. Results: Ten cases were identified from 145 eligible MSM (7%, 95% confidence interval 3–11%), comprising a rate of 3.6 per 100 person-years at risk. Cases had an annual decline in CD4 T-cell counts of 201 cells µL–1 compared with 9 cells µL–1 for controls. There were no statistically significant differences between cases and controls with regard to sexual practices that may have exposed them to acquisition of HIV superinfection (P-value ≥ 0.4), nor in their perceptions or beliefs of HIV superinfection (P-value ≥ 0.3). Only a minority reported no previous knowledge of HIV superinfection (17%, 5/30). Overall, both cases and controls were engaging frequently in unsafe sexual practices with casual partners who were HIV infected (80 and 52%, respectively P-value = 0.4) or whose HIV serostatus was unknown (40 and 50%, respectively P-value = 1.0). Conclusions: Despite considerable unsafe sexual practices occurring among this cohort of sexually active MSM the incidence of clinically significant HIV superinfection was likely to be less than 4% per year.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1093/OFID/OFW189
Abstract: In chronic human immunodeficiency virus (HIV)-1 infection, long-lived latently infected cells are the major barrier to virus eradication and functional cure. Several therapeutic strategies to perturb, eliminate, and/or control this reservoir are now being pursued in the clinic. These strategies include latency reversal agents (LRAs) designed to reactivate HIV-1 ribonucleic acid transcription and virus production and a variety of immune-modifying drugs designed to reverse latency, block homeostatic proliferation, and replenish the viral reservoir, eliminate virus-producing cells, and/or control HIV replication after cessation of antiretroviral therapy. This review provides a summary of ongoing clinical trials of HIV LRAs and immunomodulatory molecules, and it highlights challenges in the comparison and interpretation of the expected trial results.
Publisher: American Society for Clinical Investigation
Date: 27-04-2020
DOI: 10.1172/JCI130597
Publisher: Mary Ann Liebert Inc
Date: 20-01-2001
DOI: 10.1089/08892220150217238
Abstract: A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in in iduals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.
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: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2016
Publisher: American Society for Microbiology
Date: 15-05-2019
DOI: 10.1128/JVI.01901-18
Abstract: An increasing body of evidence suggests that ADCC contributes to protection against HIV-1 acquisition and slower HIV-1 disease progression. Targeting cells early during the infection cycle would be most effective in limiting virus production and spread. We hypothesized that there could be a time-dependent susceptibility of HIV-1-infected cells to ADCC in regard to CD4 expression. We observed NK cell-mediated ADCC of HIV-1-infected cells at multiple stages of CD4 downregulation. Importantly, ADCC of early infected cells appeared to be driven by a previously unappreciated problem of soluble Env and virions from the viral inoculum sensitizing uninfected cells to ADCC prior to de novo Env expression. These results have implications for studies examining ADCC against cells with nascent HIV-1 infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1998
DOI: 10.1097/00002030-199807000-00008
Abstract: To determine the relative contribution of alveolar macrophages, peripheral blood monocytes (PBM) and peripheral blood lymphocytes (PBL) from HIV-infected in iduals to HIV-1 viral load. Alveolar macrophages were obtained by flexible bronchoscopy, and PBM and PBL by venipuncture from HIV-1-infected in iduals. Alveolar macrophages and PBM were purified using immunomagnetic bead selection to deplete CD3+ and CD19+ cells from bronchoalveolar lavage and peripheral blood mononuclear cells, respectively. DNA and mRNA were extracted and gag copy number quantified using polymerase chain reaction (PCR) and reverse transcriptase PCR. The titres of infectious cell-associated HIV-1 in cells were determined by the endpoint dilution coculture technique for alveolar macrophages and PBM. Alveolar macrophages and PBM from HIV-1-infected subjects (n=11) contained equivalent concentrations of HIV-1 DNA and HIV-1 mRNA as determined by PCR and reverse transcriptase PCR, respectively. Antiretroviral therapy was associated with reduced viral DNA concentrations in alveolar macrophages but not in PBM. PBL had a significantly higher level of proviral DNA and mRNA than alveolar macrophages or PBM. Although alveolar macrophages infected in vitro are more permissive for HIV-1 replication than PBM, this difference could not be demonstrated in vivo.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1093/OFID/OFX032
Abstract: We measured human immunodeficiency virus (HIV) ribonucleic acid (RNA) in paired cerebrospinal fluid (CSF) and plasma s les in a prospective study of 91 HIV-infected, antiretroviral therapy-naive patients with cryptococcal meningitis. Cerebrospinal fluid HIV RNA was lower than in plasma (median 4.7 vs 5.2 log10 copies/mL, P & .0001) and positively correlated with plasma HIV RNA, peripheral CD4+ T-cell percentage, and CSF CXCL10. Plasma/CSF ratio of HIV RNA ranged widely from 0.2 to 265.5 with a median of 2.6. Cerebrospinal fluid quantitative cryptococcal culture positively correlated with CSF CCL2 and CCL3. CSF-plasma viral discordance was not associated with cryptococcal-associated immune reconstitution inflammatory syndrome.
Publisher: Wiley
Date: 03-2007
DOI: 10.1111/J.1442-9071.2006.01439.X
Abstract: Immune recovery uveitis (IRU) is an intraocular inflammatory disorder originally described in in iduals with human immunodeficiency virus (HIV) and inactive cytomegalovirus retinitis following highly active antiretroviral therapy. Although relatively common in in iduals with acquired immune deficiency syndrome in the United States it is an extremely uncommon presentation in Australia. IRU also occurs in iatrogenically immunosuppressed in iduals with a similar incidence to HIV-infected in iduals. We report one case of IRU in an HIV-negative in idual following a volunteer unrelated donor allogeneic stem cell transplant for non-Hodgkin's lymphoma. In the context of tapering the immunosuppression the patient developed bilateral IRU, consisting of panuveitis and macular oedema. The visual acuity (VA) at presentation of IRU was limited to counting fingers bilaterally. The IRU resolved with the re-intensification of the immunosuppression. VA restored to right 6/18 and left 6/12.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2023
Publisher: Springer Science and Business Media LLC
Date: 16-03-2020
Publisher: Elsevier BV
Date: 07-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: Oxford University Press (OUP)
Date: 07-02-2017
Publisher: Springer Science and Business Media LLC
Date: 09-10-2018
DOI: 10.1038/NRI.2017.112
Publisher: Massachusetts Medical Society
Date: 27-05-1999
Publisher: Springer Science and Business Media LLC
Date: 24-02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2008
Publisher: Wiley
Date: 02-1995
Publisher: Springer Science and Business Media LLC
Date: 08-09-2016
DOI: 10.1038/NCOMMS12731
Abstract: The ‘shock and kill’ approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected in iduals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4 + T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically erse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1.
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: 2015
Publisher: Case Western Reserve University
Date: 02-08-2017
Abstract: Background: In HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels.Methods: Thirty HIV-infected in iduals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks. All participants underwent rectal biopsies prior to starting the study drug and at 22 weeks, and there were regular blood draws. The primary end point was the change in HIV RNA and DNA levels in rectal tissue. Secondary outcomes included the change in 1) HIV levels in blood 2) Gag-specific T-cell responses 3) levels of T-cell activation and 4) collagen deposition.Results: The addition of lisinopril did not have a significant effect on the levels of HIV RNA or DNA in gut tissue or blood, Gag-specific responses, or levels of T-cell activation. Lisinopril also did not have a significant impact on lymphoid fibrosis in the rectum, as assessed by quantitative histology or heavy water labeling.Conclusions: Treatment with lisinopril for 24 weeks in HIV-infected adults did not have an effect on lymphoid fibrosis, immune activation, or gut tissue viral reservoirs. Further study is needed to see if other anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing HIV levels.Clinical Trials Registration: NCT01535235
Publisher: Informa UK Limited
Date: 15-10-2014
DOI: 10.1080/09540121.2013.845282
Abstract: Operational research to identify factors predicting poor clinical outcomes is critical to maximize patient care and prolong first-line regimens for those receiving free antiretroviral therapy (ART) in India. We sought to identify social or clinical factors amenable to intervention that predict virological outcomes after 12 months of ART. We examined a retrospective cohort of consecutive adults initiating free nonnucleoside reverse transcriptase inhibitor-based regimens. In iduals remaining in care 12 months post-ART initiation were tested for HIV viral load and surveyed to identify barriers and facilitators to adherence, and to determine clinic travel times and associated costs. Uni- and multivariate logistic regression identified factors predicting HIV viral load >200 copies/mL after 12 months of ART. Of 230 adults initiating ART, 10% of patients died, 8% transferred out, 5% were lost to follow-up, and 174/230 (76%) completed 12 months of ART, the questionnaire, and viral load testing. HIV viral load was <200 copies/mL in 140/174 (80%) patients. In multivariate models, being busy with work or caring for others (OR 2.9, p 200 copies/mL after 12 months of ART. Clinical outcomes following ART are related to programmatic factors such as prolonged travel time and in idual factors such as being busy with family or using alcohol. Simple interventions that alter these factors should be evaluated to improve clinical outcomes for populations receiving free ART in similar settings.
Publisher: Informa Healthcare
Date: 05-05-0007
DOI: 10.1517/14712598.2013.748029
Abstract: There is increasing interest in the possibility of eradication of HIV, given the recent case reports. However, it is not clear to what extent brain involvement by HIV poses a challenge to systemic eradication strategies. This review will outline the mechanisms of HIV latency, the various eradication strategies presently under consideration followed by a discussion of the issue of the frequency and severity of brain involvement by HIV. In those patients with HIV brain disease the challenges will be delineated as well as potential approaches to circumvent or minimise them. Eradication of HIV from the brain using specific methodologies is likely only needed in some patients. However, both the identification of such patients and the details of the necessary methodologies require much more research.
Publisher: Wiley
Date: 02-2009
Location: Australia
Start Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2021
Funder: National Institutes of Health
View Funded ActivityStart Date: 2015
End Date: 2018
Funder: amfAR, The Foundation for AIDS Research
View Funded ActivityStart Date: 2005
End Date: 2009
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2017
Funder: Australian Centre for HIV and Hepatitis Virology Research
View Funded Activity