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Epigenetic Mechanisms Underlying HIV-Infection Induced Susceptibility of CD4T Cells to Enhanced Activation-Induced FasL Expression and Cell Death

Journal of Acquired Immune Deficiency Syndromes, ISSN: 1077-9450, Vol: 86, Issue: 1, Page: 128-137
2021
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Background:Chronic immune activation and CD4+ T cell depletion are significant pathogenic features of HIV infection. Expression of Fas ligand (FasL), a key mediator of activation-induced cell death in T cells, is elevated in people living with HIV-1 infection (PLWH). However, the epigenetic mechanisms underlying the enhanced induction of FasL expression in CD4+ T lymphocytes in PLWH are not completely elucidated. Hence, the current work examined the effect of HIV infection on FasL promoter-associated histone modifications and transcriptional regulation in CD4+ T lymphocytes in PLWH.Method:Flow cytometric analysis was performed to examine the Fas-FasL expression on total CD4+ T cells and naïve/memory CD4+ T cell subsets. Epigenetic FasL promoter histone modifications were investigated by chromatin immunoprecipitation-quantitative real-time polymerase chain reaction analysis using freshly isolated total CD4+ T lymphocytes from HIV-1 infected and noninfected individuals.Results:All naïve/memory CD4+ T cell subsets from PLWH showed markedly greater frequency of FasL expression. Notably, examination of functional outcome of FasL/Fas co-expression demonstrated the preferential susceptibility of Tcm and Tem subsets to activation-induced apoptosis. Importantly, these CD4+ T cells collectively demonstrated a distinct FasL promoter histone profile involving a coordinated cross-talk between histone H3 modifications leading to enhanced FasL gene expression. Specifically, levels of transcriptionally permissive histone H3K4-trimethylation (H3K4Me3) and histone H3K9-acetylation (H3K9Ac) were increased, with a concomitant decrease in the repressive H3K9-trimethylation (H3K9Me3).Conclusion:The present work demonstrates that epigenetic mechanisms involving promoter-histone modifications regulate transcriptional competence and FasL expression in CD4+ T cells from PLWH and render them susceptible to activation-induced cell death.

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