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Journal of Virology, October 2009, p. 10395-10405, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00849-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Mediates Global Disruption of Innate Antiviral Signaling and Immune Defenses within Infected Cells{triangledown}

Brian P. Doehle,1 Florian Hladik,2,3,5 John P. McNevin,2 M. Juliana McElrath,2,3,4 and Michael Gale Jr.1*

University of Washington School of Medicine, Department of Immunology, Seattle, Washington 98195,1 Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,2 Departments of Medicine,3 Laboratory Medicine,4 Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington 981055

Received 27 April 2009/ Accepted 3 August 2009

Interferon regulatory factor 3 (IRF-3) is essential for innate intracellular immune defenses that limit virus replication, but these defenses fail to suppress human immunodeficiency virus (HIV) infection, which can ultimately associate with opportunistic coinfections and the progression to AIDS. Here, we examined antiviral defenses in CD4+ cells during virus infection and coinfection, revealing that HIV type 1 (HIV-1) directs a global disruption of innate immune signaling and supports a coinfection model through suppression of IRF-3. T cells responded to paramyxovirus infection to activate IRF-3 and interferon-stimulated gene expression, but they failed to mount a response against HIV-1. The lack of response associated with a marked depletion of IRF-3 but not IRF-7 in HIV-1-infected cells, which supported robust viral replication, whereas ectopic expression of active IRF-3 suppressed HIV-1 infection. IRF-3 depletion was dependent on a productive HIV-1 replication cycle and caused the specific disruption of Toll-like receptor and RIG-I-like receptor innate immune signaling that rendered cells permissive to secondary virus infection. IRF-3 levels were reduced in vivo within CD4+ T cells from patients with acute HIV-1 infection but not from long-term nonprogressors. Our results indicate that viral suppression of IRF-3 promotes HIV-1 infection by disrupting IRF-3-dependent signaling pathways and innate antiviral defenses of the host cell. IRF-3 may direct an innate antiviral response that regulates HIV-1 replication and viral set point while governing susceptibility to opportunistic virus coinfections.

* Corresponding author. Mailing address: University of Washington School of Medicine, Department of Immunology, Box 357650, Seattle, WA 98195. Phone: (206) 685-7953. Fax: (206) 643-1013. E-mail: mgale{at}u.washington.edu

{triangledown} Published ahead of print on 12 August 2009.

Journal of Virology, October 2009, p. 10395-10405, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.00849-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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