HIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of Macrophages

Bizhan Romani,Nima Shaykh Baygloo,Mojtaba Hamidi-Fard,Mohammad Reza Aghasadeghi,Elham Allahbakhshi

doi:10.1074/jbc.m115.689018

Abstract

Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here we show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. We found that Vpr binds and depletes chromatin-associated class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. De novo expression of Vpr in infected macrophages induced depletion of HDAC1 and 3 on the HIV-1 LTR that was associated with hyperacetylation of histones on the HIV-1 LTR. As a result of hyperacetylation of histones on HIV-1 promotor, the virus established an active promotor and this contributed to the acute infection of macrophages. Collectively, HIV-1 Vpr down-regulates class I HDACs on chromatin to counteract latent infections of macrophages.

Highlights

HIV-1 genome encodes 4 accessory proteins, including Nef, Vif, Vpu, and Vpr
HIV-1 Vpr Induces Depletion of Class I HDACs on Chromatin—Since Vpr-binding protein (VprBP) was reported to interact with histone deacetylase 1 (HDAC1) on chromatin, we developed a fractionation method to examine the impact of Vpr on this interaction in a localized manner
Our results indicated that depletion of class I HDACs was more drastic on chromatin as the chromatin associated class I HDACs were depleted before the soluble class I HDACs

Summary

Introduction

HIV-1 genome encodes 4 accessory proteins, including Nef, Vif, Vpu, and Vpr. These proteins are known to down-regulate cellular proteins through different mechanisms to facilitate various stages of viral infection. Chromatin Immunoprecipitation (ChIP)—To analyze enrichment of class I HDACs and acetylated histones on the HIV-1 LTR, 5 ϫ 105 MDMs were infected with pNL4.3.AD8.

Results

Conclusion