Abstract
CD8+ T cells are critical for controlling viremia during human immunodeficiency virus (HIV) infection. These cells produce cytolytic factors and antiviral cytokines that eliminate virally- infected cells. During the chronic phase of HIV infection, CD8+ T cells progressively lose their proliferative capacity and antiviral functions. These dysfunctional cells are unable to clear the productively infected and reactivated cells, representing a roadblock in HIV cure. Therefore, mechanisms to understand CD8+ T cell dysfunction and strategies to boost CD8+ T cell function need to be investigated. Using the feline immunodeficiency virus (FIV) model for lentiviral persistence, we have demonstrated that CD8+ T cells exhibit epigenetic changes such as DNA demethylation during the course of infection as compared to uninfected cats. We have also demonstrated that lentivirus-activated CD4+CD25+ T regulatory cells induce forkhead box P3 (Foxp3) expression in virus-specific CD8+ T cell targets, which binds the interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ promoters in these CD8+ T cells. Finally, we have reported that epigenetic modulation reduces Foxp3 binding to these promoter regions. This review compares and contrasts our current understanding of CD8+ T cell epigenetics and mechanisms of lymphocyte suppression during the course of lentiviral infection for two animal models, FIV and simian immunodeficiency virus (SIV).
Highlights
CD8+ T lymphocytes (CTLs) play a critical role in the control of human immunodeficiency virus (HIV) infection [1,2]
We have demonstrated that forkhead box P3 (Foxp3) mediates antiviral cytokine suppression by directly binding to IL-2, tumor necrosis factor (TNF)-α and IFN-γ promoter region in the acute and chronic phase of feline immunodeficiency virus (FIV)
We have demonstrated that during FIV infection, CD8+ T cells directly interact with lentivirus activated Treg cells via a membrane bound tumor growth factor (TGF)-β mechanism, inducing Foxp3 in these cells [113,114]
Summary
CD8+ T lymphocytes (CTLs) play a critical role in the control of human immunodeficiency virus (HIV) infection [1,2]. In HIV infection and the rhesus macaque model of simian immunodeficiency virus (SIV) infection, checkpoint inhibitors targeting these molecules can partially restore CD8+ T cell function [17,18,19] These studies provide proof-of-concept for the feasibility of developing effective immune strategies to enhance CD8 + T cell function in vivo. Foxp3+ Treg cells can be induced in vitro by T-cell receptor (TCR)-mediated activation of naïve CD4+ CD25− T cells in the presence of TGF-β and IL-2 [82,83] They regulate the immune response by inhibiting T cell proliferation by competing for the growth factor IL-2, by CTLA-4 binding to dendritic cells (DCs), through the secretion of inhibitory cytokines such as IL-10 and TGF-β, and utilizing cytolytic molecules such as granzyme B and perforin [84]. This review will focus on the immunosuppressive function of Treg cells, but we acknowledge that Treg cells can have beneficial effects on HIV infection and control, as reported by other investigators (reviewed in Moreno et al [110])
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