Document Type

Article

Publication Date

1-1-2021

Department

Medicine

Department

Epidemiology and Population Health

Abstract

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.

Original Publication Information

Ghare, Smita S. PhDa,b; Chilton, Paula M. PhDa,b; Rao, Aakarsha V. MSa; Joshi-Barve, Swati PhDa,c,b; Peyrani, Paula MDa,b; Reyes Vega, Andrea MDa,b; McClain, Craig J. MDa,c,b; Bryant, Kendall PhDd; Cook, Robert L. MDe; Freiberg, Mathew MDf; Barve, Shirish PhDa,c,b. Epigenetic Mechanisms Underlying HIV-Infection Induced Susceptibility of CD4+ T Cells to Enhanced Activation-Induced FasL Expression and Cell Death. JAIDS Journal of Acquired Immune Deficiency Syndromes 86(1):p 128-137, January 1, 2021.

DOI

doi:10.1097/QAI.0000000000002526

ORCID

0000-0003-1633-6097

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