B-101 Unique features of effector to memory transition render CD4+ T cells permissive for latent HIV infection

2016 ◽  
Vol 71 ◽  
pp. 40
Author(s):  
Robert Siliciano
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Latent Hiv

scholarly journals Shared Mechanisms Govern HIV Transcriptional Suppression in Circulating CD103+ and Gut CD4+ T Cells

2020 ◽  
Vol 95 (2) ◽  
pp. e01331-20
Author(s):  
Steven A. Yukl ◽  
Shahzada Khan ◽  
Tsui-Hua Chen ◽  
Martin Trapecar ◽  
Frank Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Hiv Latency ◽  
Expression Levels ◽  
Hiv Rna ◽  
Infected Cells ◽  
Latent Hiv ◽  
Main Barrier

ABSTRACTLatent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103− CD4 T cells from the blood and rectum of HIV-negative (HIV−) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103− cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103− cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, “latent” infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103− T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.

scholarly journals Impact of Biological Sex on Immune Activation and Frequency of the Latent HIV Reservoir During Suppressive Antiretroviral Therapy

2020 ◽  
Vol 222 (11) ◽  
pp. 1843-1852 ◽  
Author(s):  
Shane D Falcinelli ◽  
Bonnie E Shook-Sa ◽  
Morgan G Dewey ◽  
Sumati Sridhar ◽  
Jenna Read ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
Interferon Response ◽  
Suppressive Therapy ◽  
Hiv Reservoir ◽  
Latent Hiv

Abstract Background Persistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to HIV cure. Women have a more robust type 1 interferon response during HIV infection relative to men, contributing to lower initial plasma viremia. As lower viremia during acute infection is associated with reduced frequency of latent HIV infection, we hypothesized that women on ART would have a lower frequency of latent HIV compared to men. Methods ART-suppressed, HIV seropositive women (n = 22) were matched 1:1 to 22 of 39 ART-suppressed men. We also compared the 22 women to all 39 men, adjusting for age and race as covariates. We measured the frequency of latent HIV using the quantitative viral outgrowth assay, the intact proviral DNA assay, and total HIV gag DNA. We also performed activation/exhaustion immunophenotyping on peripheral blood mononuclear cells and quantified interferon-stimulated gene (ISG) expression in CD4 T cells. Results We did not observe evident sex differences in the frequency of persistent HIV in resting CD4 T cells. Immunophenotyping and CD4 T-cell ISG expression analysis revealed marginal differences across the sexes. Conclusions Differences in HIV reservoir frequency and immune activation appear to be small across sexes during long-term suppressive therapy.

scholarly journals Lymphatic endothelial cells promote productive and latent HIV infection in resting CD4+ T cells

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Meghan Schilthuis ◽  
Seth Verkaik ◽  
Mackenzie Walhof ◽  
Andrew Philipose ◽  
Olivia Harlow ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Lymphatic Endothelial Cells ◽  
Latent Hiv

scholarly journals The CCL2 Chemokine Promotes Early Seeding of the Latent HIV Reservoir

2021 ◽  
Author(s):  
Thomas A. Packard ◽  
Roland Schwarzer ◽  
Eytan Herzig ◽  
Deepashri Rao ◽  
Xiaoyu Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Central Memory ◽  
Humanized Mice ◽  
Hiv Reservoir ◽  
Latent Hiv ◽  
Memory Cd4 T Cells

ABSTRACTHIV infects long-lived CD4 memory T cells establishing a latent viral reservoir that necessitates lifelong anti-retroviral therapy (ART). How this reservoir is formed so swiftly remains unknown. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, which can drive recruitment of cells expressing the CCR2 receptor including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find 1) treatment of humanized mice with anti-CCL2 antibodies during HIV infection decreases reservoir seeding and 2) CCR2/5+ cells from the blood of HIV-infected individuals on long term ART contain significantly more provirus than CCR2/5-negative memory or naïve cells. Together, these studies support a model where the host’s innate inflammatory CCL2 response to HIV infection recruits CCR2/5+ central memory CD4 T cells to zones of virus-associated inflammation likely contributing to rapid formation of the latent HIV reservoir.GRAPHICAL ABSTRACTWhy is the latent HIV reservoir established so early following infection? An innate immune response occurs during acute infection that establishes a “zone of inflammation” (step 1). The CCL2 chemokine is produced in part through IFI16 sensing of HIV DNA in abortively infected cells. CCL2 promotes rapid recruitment of CCR2/5+ memory CD4 T cells (step 2). Many of these cells become productively infected (step 3) and a fraction become latently infected (step 4). Thus, HIV hijacks the host inflammatory response to rapidly establish the latent reservoir. In support of this model, we find HIV reservoir reduction in humanized mice treated with anti-CCL2 antibodies during early infection. Further, we find that CCR2/5+ CD4 T cells harbor a substantial fraction of detectable proviruses in the blood of HIV-infected individuals on long-term suppressive ART.Abstract Figure

Circulating integrin α 4 β 7 + CD4 T cells are enriched for proliferative transcriptional programs in HIV infection

FEBS Letters ◽  
2021 ◽  
Author(s):  
Yashavanth S. Lakshmanappa ◽  
Jamin W. Roh ◽  
Niharika N. Rane ◽  
Ashok R. Dinasarapu ◽  
Daphne D. Tran ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells

scholarly journals Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simon X. M. Dong ◽  
Frederick S. Vizeacoumar ◽  
Kalpana K. Bhanumathy ◽  
Nezeka Alli ◽  
Cristina Gonzalez-Lopez ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Respiratory Chain ◽  
Cd4 T Cells ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Complex Ii ◽  
Genome Wide ◽  
Latently Infected ◽  
Induced Apoptosis

Abstract Background Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. Methods We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student’s t-test from at least four independent experiments. Results We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. Conclusions We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

scholarly journals Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells

2017 ◽  
Vol 13 (2) ◽  
pp. e1006163 ◽  
Author(s):  
Jason A. Neidleman ◽  
Joseph C. Chen ◽  
Nargis Kohgadai ◽  
Janis A. Müller ◽  
Anders Laustsen ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Stromal Fibroblasts
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