Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1:: Role of type IIFN-producing plasmacytoid dendritic cells
Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1:: Role of type IIFN-producing plasmacytoid dendritic cells
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DOI：
10.1073/pnas.0505251102
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发表时间：
2005-09-27
影响因子：
11.1
通讯作者：
Shearer, GM
中科院分区：
文献类型：
--
作者：
Herbeuval, JP;Hardy, AW;Shearer, GM
TNF相关凋亡诱导配体（TRAIL）是TNF超家族的一员，被认为通过诱导艾滋病特征的CD4(+) T细胞死亡来促进HIV-1的发病。我们之前报道了hiv -1介导的、TRAIL诱导的原代CD4+ T细胞体外凋亡，并观察到hiv -1感染患者血浆TRAIL水平升高。本研究阐明了HIV-1诱导原代CD4(+) T细胞上TRAIL表达的尚未解决的机制。我们证明，原代CD4+ T细胞的TRAIL表达受到由hiv -1刺激的浆细胞样树突状细胞（pDCs）产生的ifn - α的调节。我们还发现ifn诱导的TRAIL是由转录1和2的信号转导和激活因子介导的。我们发现hiv -1激活的pDCs产生的IFN-a被CD4-gp120结合的早期病毒进入抑制剂阻断，而不是被病毒辅受体结合的抑制剂阻断。我们的体外数据得到了抗ifn - α和- β抗体抑制hiv -1感染患者CD4+ T细胞凋亡和TRAIL表达的支持。我们的研究结果表明，通过诱导死亡分子TRAIL， pDCs在HIV-1感染的免疫发病机制中具有潜在的独特作用。
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4(+) T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4+ T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4(+) T cells. We demonstrate that the expression of TRAIL by primary CD4+ T cells is regulated by IFN-alpha that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-a production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-alpha and -beta Abs inhibit apoptosis and TRAIL expression in CD4+ T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immunopathogenesis of HIV-1 infection by inducing the death molecule TRAIL.