TRAF6 and IRF7 Control HIV Replication in Macrophages

Mélissa Sirois,Lynda Robitaille,Christopher H Woelk,Mohak Shah,Jérôme Estaquier,Jacques Corbeil,Robin Allary,Fabrizio Mammano

doi:10.1371/journal.pone.0028125

Abstract

The innate immune system recognizes virus infection and evokes antiviral responses which include producing type I interferons (IFNs). The induction of IFN provides a crucial mechanism of antiviral defense by upregulating interferon-stimulated genes (ISGs) that restrict viral replication. ISGs inhibit the replication of many viruses by acting at different steps of their viral cycle. Specifically, IFN treatment prior to in vitro human immunodeficiency virus (HIV) infection stops or significantly delays HIV-1 production indicating that potent inhibitory factors are generated. We report that HIV-1 infection of primary human macrophages decreases tumor necrosis factor receptor-associated factor 6 (TRAF6) and virus-induced signaling adaptor (VISA) expression, which are both components of the IFN signaling pathway controlling viral replication. Knocking down the expression of TRAF6 in macrophages increased HIV-1 replication and augmented the expression of IRF7 but not IRF3. Suppressing VISA had no impact on viral replication. Overexpression of IRF7 resulted in enhanced viral replication while knocking down IRF7 expression in macrophages significantly reduced viral output. These findings are the first demonstration that TRAF6 can regulate HIV-1 production and furthermore that expression of IRF7 promotes HIV-1 replication.

Highlights

Infection by RNA viruses, such as human immunodeficiency virus (HIV)-1, initiates antiviral innate immune responses by inducing type I IFNs [1,2]
To ascertain the stage at which HIV-1 replication was curtailed in the IFNa2 pre-treated macrophages, we monitored viral replication by quantifying TAT spliced message expression by quantitative RT-PCR (qRT-PCR), a marker of productive viral transcription distinct from incoming viral genomic RNA
Kinetic was greatly delayed in IFNa2 pre-treated macrophages infected with HIV-1, where initial detection was observed at 120 hours and subsequently increased over time (Fig. 1)

Summary

Introduction

Infection by RNA viruses, such as HIV-1, initiates antiviral innate immune responses by inducing type I IFNs [1,2]. Pre-treatment is not a viable clinical option and, innate immune responses in vivo fail to completely protect the human host even though genes integral to host defense are expressed. This may be due to the deregulation by HIV-1 of the signaling events necessary for induction of an appropriate innate immune response mediated by IFN or that HIV-1 replication outpaces these defenses. It has been shown that the level of Type I IFN correlates with AIDS pathogenesis [19]

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