Type I Interferons and Interferon Regulatory Factors Regulate TNF-Related Apoptosis-Inducing Ligand (TRAIL) in HIV-1-Infected Macrophages

Yunlong Huang,Jialin C Zheng,Yong Zhao,Angelique Walstrom,Luwen Zhang,Ling Ye,Min Cui,Derya Unutmaz

doi:10.1371/journal.pone.0005397

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that participates in HIV-1 pathogenesis through the depletion of CD4+ T cells. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The regulation of TRAIL in macrophages during HIV-1 infection is not completely understood. In this study, we investigated the mechanism(s) of TRAIL expression in HIV-1-infected macrophages, an important cell type in HIV-1 pathogenesis. A human monocyte-derived macrophage (MDM) culture system was infected with macrophage-tropic HIV-1ADA, HIV-1JR-FL, or HIV-1BAL strains. TRAIL, predominantly the membrane-bound form, increased following HIV-1 infection. We found that HIV-1 infection also induced interferon regulatory factor (IRF)-1, IRF-7 gene expression and signal transducers and activators of transcription 1 (STAT1) activation. Small interfering RNA knockdown of IRF-1 or IRF-7, but not IRF-3, reduced STAT1 activation and TRAIL expression. Furthermore, the upregulation of IRF-1, IRF-7, TRAIL, and the activation of STAT1 by HIV-1 infection was reduced by the treatment of type I interferon (IFN)-neutralizing antibodies. In addition, inhibition of STAT1 by fludarabine abolished IRF-1, IRF-7, and TRAIL upregulation. We conclude that IRF-1, IRF-7, type I IFNs, and STAT1 form a signaling feedback loop that is critical in regulating TRAIL expression in HIV-1-infected macrophages.

Highlights

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and an important immune regulatory factor capable of inducing apoptosis [1,2,3]
Upregulation of TRAIL expression by HIV-1-infected macrophages has been previously reported [7,10]; our current study investigated the mechanisms behind this upregulation
The investigated macrophage-tropic viral strains all strongly upregulated TRAIL expression levels as indicated by real-time reverse-transcription polymerase chain reaction (RT-PCR), and this upregulation was blocked by reverse transcriptase inhibitor AZT (Fig. 1B)

Summary

Introduction

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and an important immune regulatory factor capable of inducing apoptosis [1,2,3]. The plasma levels of TRAIL are increased in HIV-1-infected patients compared to uninfected individuals, and patients receiving anti-retroviral therapy show decreased plasma TRAIL levels that correlate with reduced viral load [5]. Increased TRAIL expression is an important contributor to HIV-1-mediated apoptosis in bystander CD4+ T cells [6,7,8,9]. Recombinant human TRAIL has been found to induce apoptosis in HIV-1-infected macrophages and cultured neurons as we have previously reported [10,11]. The apoptotic signaling events of TRAIL have been studied extensively, including our recent work [10,11,12,13], the upstream molecular stimuli, those that are responsible for HIV-1-mediated TRAIL upregulation, remain unclear

Methods

Results

Conclusion