HIV-1 efficiently promotes infection through its ability to evade and disable the first anti-viral immune responses provided by the innate immune system. However, researchers do not understand how HIV-1 hinders innate immune responses. To better understand how HIV evades immune defenses, University of Washington senior fellow Dr. Brian Doehle and VIDI colleagues, including VIDI member Dr. Julie McElrath and VIDI affiliate investigator Dr. Michael Gale, Jr. examined cellular signaling components of the innate immune system during HIV infection of CD4+ T cells (a type of immune cell that is the primary target of HIV infection).
Doehle and colleagues found that HIV-1 globally disrupts innate immune signaling by suppressing interferon regulatory factor 3 (IRF-3), a key protein in the innate immune response that allows cells to recognize the presence of pathogens. Using cultures of human CD4+ T cells, the authors found that cells infected with HIV had reduced amounts of the IRF-3 protein and disrupted signaling in key components of the innate immune system – specifically the pathogen recognition receptor (PRR) pathways and interferon-stimulated genes. Finally, the researchers also found that forcing additional expression of a constantly active version of IRF-3 suppressed HIV-1 infection in T cells.
To determine if these findings were relevant to clinical infection, the scientists analyzed IRF-3 expression in tissues and cells from HIV positive and negative volunteers. Compared to the immune cells from uninfected individuals, CD4+ T cells from individuals with acute HIV-1 infections had reduced IRF-3 levels, whereas no difference in IRF-3 levels was detected in the CD4+ T cells from HIV-1 infected individuals who have not progressed to AIDS (long term non-progressors).
Together this work indicates that HIV suppression of IRF-3 promotes infection by disrupting IRF-3 signaling pathways that are essential to innate antiviral defenses. Specifically, the finding that activation of IRF-3 can suppress HIV-1 infection suggests that either IRF-3 activation or the restoration of IRF-3 protein expression may be a new direction for the design of future HIV therapeutics.
Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. Doehle BP, Hladik F, McNevin JP, McElrath MJ, Gale M Jr. J Virol. 2009 Oct;83(20):10395-405.