%0 Journal Article
%T Type I Interferons and Interferon Regulatory Factors Regulate TNF-Related Apoptosis-Inducing Ligand (TRAIL) in HIV-1-Infected Macrophages
%A Yunlong Huang
%A Angelique Walstrom
%A Luwen Zhang
%A Yong Zhao
%A Min Cui
%A Ling Ye
%A Jialin C. Zheng
%J PLOS ONE
%D 2009
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0005397
%X 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005397