Plasmacytoid Dendritic Cells in HIV Pathogenesis

描述（由申请人提供）：在晚期HIV-1感染患者中观察到天然ifn产生细胞（NIPC）产生干扰素-a （IFN-a）的缺陷。这种缺乏IFN-a的生产被发现与机会性感染的易感性有关，并可预测。虽然长期以来被怀疑是树突状细胞，但由于缺乏明确的NIPC表型，进展受到一定程度的阻碍。NIPC现已被证明与浆细胞样树突状细胞（PDC）相同。PDC不仅是专业的IPC，而且是先天免疫和适应性免疫之间的重要联系。HIV感染中IFN-a产生不足的原因是循环PDC数量的减少以及这些细胞的功能障碍。目前的研究有五个具体目标；前三项涉及PDC的基本生物学研究，后两项应用已经了解的PDC的功能来了解它们如何在艾滋病毒感染患者中变得缺乏。外周血PDC表达非常高水平的转录因子IRF-7。这些观察结果将扩展到评估不同解剖部位PDC中IRF-7的表达和功能，并确定IRF-7与IRF-3和IRF- 5在这些细胞中的作用。PDC表面受体的交联导致其产生IFN-a的能力下调，这一现象在hiv感染患者中也可能具有生理相关性。研究旨在了解这种下调的机制，并确定PDC的其他功能，如TNF-a和趋化因子的产生是否同样受到受体交联的影响。PDC产生IFN-a不需要病毒感染细胞；相反，内吞作用对物质的摄取似乎触发了IFN-a的产生。利用荧光标记的感染细胞或病毒和共聚焦显微镜，将确定内吞物质在体内的命运。为了更好地了解艾滋病毒感染患者PDC缺乏的机制，将开展研究，以确定PDC是否在体内感染了艾滋病毒，以及它们是否从血液转运到组织中的部位。最后，研究人员提出评估PDC在HIV-1感染患者中的其他功能，包括细胞因子和趋化因子的产生和T细胞的激活，以及评估IRF-7在这些细胞中的功能。

DESCRIPTION (provided by applicant): Deficient production of interferon-a (IFN-a) by natural IFN-producing cells (NIPC) is observed in patients with advanced HIV-1 infection. This deficient IFN-a production was found to be associated with, and predictive of, susceptibility to opportunistic infections. Although long-suspected to be a dendritic cell, progress was somewhat hampered by the lack of a definitive phenotype for the NIPC. NIPC have now been demonstrated to be identical to the plasmacytoid dendritic cell (PDC). PDC's are believed to be important not only as professional IPC but also as vital links between innate and adaptive immunity. Deficient IFN-a production in HIV infection results from both decreases in numbers of circulating PDC as well as dysfunction in those cells present. This current study is organized in five specific aims; the first three involve studies of the basic biology of the PDC and the last two apply what has been learned about the function of PDC's to understand how they become deficient in HIV infected patients. Peripheral blood PDC's express very high constitutive levels of the transcription factor, IRF-7. These observations will be extended to evaluate the expression and function of the IRF-7 in PDC's in different anatomical sites and determine the roles of IRF-7 vs. IRF-3 and IRF- 5 in these cells. Cross-linking of receptors on the surface of PDC leads to down-regulation of their ability to produce IFN-a, a phenomenon that may also have physiological relevance in the HIV-infected patients. Studies are proposed to understand the mechanisms of this down-regulation and determine whether other functions carried out by PDC such as production of TNF-a and chemokines is similarly affected by the receptor crosslinking. Production of IFN-a by PDC's does not require infection of the cells with virus; rather uptake of material by endocytosis appears to trigger the generation of IFN-a. Using fluorescent labeled infected cells or virus and confocal microscopy, the fate of the endocytosed material in vivo will be determined. In studies to better understand the mechanisms of deficiency in PDC in HIV-infected patients, studies will be undertaken to determine whether PDC's are infected with HIV in vivo and whether they traffick from the blood to sites in the tissues. Finally studies are proposed to evaluate other functions of the PDC in HIV-1 infected patients including cytokine and chemokine production and activation of T cells as well evaluation of the IRF-7 function in these cells.