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HIV-1 gp120 inhibits TLR9-mediated activation and IFN-α secretion in plasmacytoid dendritic cells

Martinelli, Elena, Cicala, Claudia, Van Ryk, Donald, Goode, Diana J., Macleod, Katilyn, Arthos, James, Fauci, Anthony S.
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.9 pp. 3396-3401
CCR5 receptor, CD4-positive T-lymphocytes, CXCR4 receptor, HIV infections, Human immunodeficiency virus 1, Toll-like receptor 7, Toll-like receptor 9, adaptive immunity, cytokines, dendritic cells, immune response, interferon-alpha, natural killer cells, pathogens, secretion, viral load
Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses against viral infections. pDCs secrete type I IFNs and proinflammatory cytokines upon stimulation by either TLR7 or TLR9. Throughout the course of HIV infection, the production of type-I IFNs is profoundly impaired, and total pDC cell counts in peripheral blood correlates inversely with viral load and positively with CD4⁺ T cell count. The origin of these defects is unclear. pDCs express CD4, CCR5, and CXCR4, the primary receptor and coreceptors, respectively, for the HIV envelope; yet little is known concerning the effects of the viral envelope on these cells. Here, we show that exposure of pDCs to gp120 results in the suppression of activation of these cells. This suppression is specific for TLR9-mediated responses, because TLR7-mediated responses are unaffected by gp120. gp120 also suppressed TLR9-mediated induction of proinflammatory cytokines and expression of CD83, a marker of DC activation. Finally, gp120 suppressed pDC-induced cytolytic activity of natural killer cells. Taken together, these data demonstrate that the direct interaction of HIV-1 gp120 with pDCs interferes with TLR9 activation resulting in a decreased ability of pDCs to secrete antiviral and inflammatory factors that play a central role in initiating host immune responses against invading pathogens.