HIV-1 envelope glycoprotein stimulates viral transcription and increases the infectivity of the progeny virus through the manipulation of cellular machinery

Xiaozhuo Ran,Xiaojian Yao,Wayne Xu,Gary Kobinger,Zhujun Ao,Adriana Trajtman,Yoav Keynan

doi:10.1038/s41598-017-10272-7

Abstract

During HIV infection, large amounts of progeny viral particles, including infectious virus and a large proportion of defective viral particles, are produced. Despite of the critical role of the infectious viruses in infection and pathogenesis in vivo, whether and how those defective viral particles, especially the virus-associated envelope glycoprotein (vEnv), would impact viral infection remains elusive. In this study, we investigated the effect of vEnv on HIV-infected T cells and demonstrated that the vEnv was able to stimulate HIV transcription in HIV-infected cells, including peripheral blood mononuclear cells (PBMCs) isolated from HIV patients. This vEnv-mediated HIV transcription activation is mediated primarily through the interaction between vEnv and CD4/coreceptors (CCR5 or CXCR4). Through transcriptome analysis, we found that numerous cellular gene products involved in various signaling pathways were modulated by vEnv. Among them, we have further identified a cellular microRNA miR181A2, which is downregulated upon vEnv treatment, resulting in increased HIV LTR histone H3 acetylation and HIV transcription. Furthermore, we also found a vEnv-modulated cellular histone deacetylase, HDAC10, whose downregulation is associated with the increased infectivity of progeny viruses. Altogether, these findings provide evidence of the important role vEnv plays in modulating cellular environments and facilitating HIV expression and infection.

Highlights

It is well known that during HIV infection, infected cells produce infectious viruses and large amounts of noninfectious or defective particles as a result of highly reading-frame-error-prone reverse transcriptase[1, 2]
When equal amounts of progeny viruses derived from the histone deacetylase 10 (HDAC10)-KD Jurkat T cells and the control T cells were used to infect the C8166 T cells, CEM-SS T cells and TZMb1 cells, we found that viruses produced from the HDAC10-KD Jurkat T cells mediated significantly higher levels of infection than the control Jurkat T cells (Fig. 6C), indicating that the infectivity of progeny viruses produced from the HDAC10-KD Jurkat T cells were significantly enhanced
Numerous studies have shown that these defective particles, especially the envelope glycoprotein present on these viral particles, significantly contribute to HIV pathogenesis in vivo[1, 45], their roles and the mechanisms by which these virus-associated Env affect viral expression and late-stage viral replication remain elusive

Summary

Introduction

It is well known that during HIV infection, infected cells produce infectious viruses and large amounts of noninfectious or defective particles as a result of highly reading-frame-error-prone reverse transcriptase[1, 2]. CD4/co-receptors led to activation of cellular pathways including cell adhesion, proliferation and actin modulation[7, 17, 18], and the elevated expression of cytokines and chemokines[18]; Other studies suggest that gp[120] could interfere with CD4 costimulatory functions and induces apoptosis[19]. All of these studies provide evidence of the important role of HIV gp[120] in the establishment of HIV infection and its induced pathogenesis. We have demonstrated HIV vEnv was able to suppress the cellular histone deacetylase 10 (HDAC10) expression and its downregulation led to an increased infectivity of the produced progeny virus

Methods

Results

Conclusion