Epigenetic mechanisms underlying HIV-infection induced susceptibility of CD4+ T cells to enhanced activation-induced FasL expression and cell death.

Authors

Smita Ghare, University of Louisville
Paula M. Chilton, University of Louisville
Aakarsha V. Rao, University of Louisville
Swati Joshi-Barve, University of Louisville
Paula Peyrani, University of LouisvilleFollow
Andrea Reyes-Vega, University of LouisvilleFollow
Craig J. McClain, University of Louisville
Kendall Bryant
Robert L. Cook, University of Florida
Mathew Freiberg, Vanderbilt University
Shirish Barve, University of Louisville

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.

ThinkIR Citation

Ghare, Smita; Chilton, Paula M.; Rao, Aakarsha V.; Joshi-Barve, Swati; Peyrani, Paula; Reyes-Vega, Andrea; McClain, Craig J.; Bryant, Kendall; Cook, Robert L.; Freiberg, Mathew; and Barve, Shirish, "Epigenetic mechanisms underlying HIV-infection induced susceptibility of CD4+ T cells to enhanced activation-induced FasL expression and cell death." (2021). Faculty Scholarship. 957.
https://ir.library.louisville.edu/faculty/957

DOI

doi:10.1097/QAI.0000000000002526

ORCID

0000-0003-1633-6097