Martinelli Elena, Cicala Claudia, Van Ryk Donald, Goode Diana J, Macleod Katilyn, Arthos James, Fauci Anthony S
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3396-401. doi: 10.1073/pnas.0611353104. Epub 2007 Feb 20.
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.
浆细胞样树突状细胞（pDCs）在针对病毒感染的固有免疫和适应性免疫反应中发挥核心作用。pDCs在受到TLR7或TLR9刺激后会分泌I型干扰素和促炎细胞因子。在整个HIV感染过程中，I型干扰素的产生严重受损，外周血中pDC的细胞总数与病毒载量呈负相关，与CD4(+) T细胞计数呈正相关。这些缺陷的起源尚不清楚。pDCs分别表达HIV包膜的主要受体和共受体CD4、CCR5和CXCR4；然而，关于病毒包膜对这些细胞的影响知之甚少。在这里，我们表明pDCs暴露于gp120会导致这些细胞的激活受到抑制。这种抑制对TLR9介导的反应具有特异性，因为TLR7介导的反应不受gp120影响。gp120还抑制了TLR9介导的促炎细胞因子的诱导以及DC激活标志物CD83的表达。最后，gp120抑制了pDC诱导的自然杀伤细胞的细胞溶解活性。综上所述，这些数据表明HIV-1 gp120与pDCs的直接相互作用会干扰TLR9的激活，导致pDCs分泌抗病毒和炎症因子的能力下降，而这些因子在启动宿主针对入侵病原体的免疫反应中起核心作用。
