Regulation of human immunodeficiency virus type 1 latency by histone deacetylases.

摘要

Despite highly effective antiretroviral therapies capable of suppressing plasma viremia, human immunodeficiency virus type 1 (HIV-1) persists in latent reservoirs in the millions of infected individuals worldwide. A significant contributor to viral persistence is the ability of the HIV-1 genome to stably integrate into the DNA of resting CD4+ T cells and adopt a state of latency, evading both immune detection and pharmaceutical attack. Once integrated, HIV-1 resides in the host chromatin environment where DNA is packaged around histones. Histone deacetylases (HDACs) are a family of 11 enzymes that can deacetylate histone tails, creating a repressive chromatin environment unfavorable to transcription. Enzymatic inhibition of HDACs with pan-HDAC inhibitors can reactivate latent HIV-1. However, the specific HDAC isoforms that regulate transcription from the HIV-1 5' long-terminal repeat (LTR) promoter during latency have not been completely defined.;In this dissertation, I hypothesized that specific HDACs are recruited to the HIV-1 LTR during latency to maintain transcriptional repression. Using chromatin immunoprecipitation assays, I showed that the class I HDACs HDAC1, -2, and -3 are recruited to the HIV-1 LTR in the J89 cell line model of HIV-1 latency. These HDACs were highly expressed in the nuclei of resting CD4+ T cells, the primary latent HIV-1 reservoir. Targeted depletion of HDAC2 or HDAC3 using siRNA led to induction of HIV-1 expression in latency cell line models. However, simultaneous knockdown of HDAC1, -2, and -3 abolished this effect. In contrast, HDAC inhibitors that target HDAC1, -2, and -3 in tandem were potent inducers of latent HIV-1, suggesting a mechanistic difference between HDAC knockdown and enzymatic inhibition. When HDAC1, -2, or -3 were knocked down in resting CD4+ T cells isolated from aviremic, HIV-1-infected patients, we observed outgrowth of a selected number of proviral integrants. Collectively, these findings suggest that HDAC inhibitors that target a limited number of class I HDACs, specifically some combination of HDAC1, -2, and -3, may be effective antilatency therapies.