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

Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses against viral infections. pDCs secrete type I IFNs and proinflarnmatory cytokines upon stimulation by either TLR7 or TLR9. Throughout the course of HIV infection, the production of type-I IFINs 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. pIDCs express C1134, 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 TI-1119-mediated induction of proinflarnmatory 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 pIDCs 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.