Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells.

Publication Type:

Journal Article

Source:

Journal of virology, Volume 83, Issue 20, p.10395-405 (2009)

Keywords:

2009, Antibody Development Core Facility, CD4-Positive T-Lymphocytes, Cell Line, Cells, Cultured, Center-Authored Paper, DEAD-box RNA Helicases, Female, Flow Cytometry Core Facility, HIV Infections, HIV-1, Humans, Immunity, Innate, Interferon Regulatory Factor-3, Leukocytes, Mononuclear, Shared Resources, Signal Transduction, Toll-Like Receptors, Vaccine and Infectious Disease Institute, Virus Replication

Abstract:

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.