Endocytosis of HIV-1 activates plasmacytoid dendritic cells via toll-like receptor-viral RNA interactions
Endocytosis of HIV-1 activates plasmacytoid dendritic cells via toll-like receptor-viral RNA interactions
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DOI：
10.1172/jci26032
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Bhardwaj, N
中科院分区：
文献类型：
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作者：
Beignon, AS;McKenna, K;Bhardwaj, N
HIV-1通过上调共刺激和MHC分子的表达和成熟标记，从而直接激活人浆细胞类动物DC（PDC），从而增加T细胞刺激活性，并诱导I型Interferons和TNF-Alpha的产生。这种激活的结果是髓样DC的旁观者成熟和抗原呈递功能的总体增强。但是，HIV-1激活PDC激活的机制知之甚少。在这里，我们通过体外研究证明，PDC对HIV-1产生的IFN-α产生需要细胞与病毒之间的至少2个相互作用。最初，通过使用结合，融合，内吞作用和内体酸化的抑制剂证明，包膜CD4相互作用介导HIV-1的内吞作用。随后，随着用纯化的基因组RNA而非病毒RNA包装缺陷型HIV-1再现激活，内体递送的病毒核酸，尤其是RNA，刺激PDC，并用不同的抑制性TLR TLR配体封闭。最后，通过使用遗传互补，我们表明TLR7可能是主要目标。在早期逆转录中，病毒RNA而不是DNA似乎是HIV-1中诱导PDC分泌IFN-Alpha的活性因子。由于慢性HIV-1感染中PDC的下降与高病毒载荷和机会性感染有关，因此利用HIV-1 RNA的这种天然辅助活性可能有助于开发预防艾滋病的疫苗。
HIV-1 directly activates human plasmacytoid DCs (pDCs) by upregulating the expression of costimulatory and MHC molecules and maturation markers, increasing T cell stimulatory activity, and inducing the production of type I interferons and TNF-alpha. A consequence of this activation is the bystander maturation of myeloid DCs and overall enhancement of antigen-presenting function. However, little is known about the mechanism(s) of pDC activation by HIV-1. Here we demonstrate by in vitro studies that IFN-alpha production by pDC in response to HIV-1 requires at least 2 interactions between the cell and virus. Initially, envelope-CD4 interactions mediate endocytosis of HIV-1, as demonstrated through the use of inhibitors of binding, fusion, endocytosis, and endosomal acidification. Subsequently, endosomally delivered viral nucleic acids, particularly RNA, stimulate pDCs through TLRs, as activation is reproduced with purified genomic RNA but not viral RNA packaging-deficient HIV-1 and blocked with different inhibitory TLR ligands. Finally, by using genetic complementation, we show that TLR7 is the likely primary target. Viral RNA rather than DNA in early retrotranscripts appears to be the active factor in HIV-1 that induces IFN-alpha secretion by pDCs. Since the decline in pDCs in chronic HIV-1 infection is associated with high viral loads and opportunistic infections, exploiting this natural adjuvant activity of HIV-1 RNA might be useful in the development of vaccines for the prevention of AIDS.