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PLoS One. 2009;4(4):e5397. doi: 10.1371/journal.pone.0005397. Epub 2009 Apr 30.

Type I interferons and interferon regulatory factors regulate TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected macrophages.

Author information

1
Department of Pharmacology and Experimental Neuroscience, Laboratory of Neurotoxicology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

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-1(ADA), HIV-1(JR-FL), or HIV-1(BAL) 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.

PMID:
19404407
PMCID:
PMC2672636
DOI:
10.1371/journal.pone.0005397
[Indexed for MEDLINE]
Free PMC Article

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