Plasmacytoid Dendritic Cells in HIV Pathogenesis

描述（由申请方提供）：在晚期HIV-1感染患者中观察到天然干扰素产生细胞（NIPC）产生干扰素-a（IFN-a）不足。发现这种IFN-α产生的缺陷与机会性感染的易感性相关，并可预测机会性感染的易感性。虽然长期以来怀疑是树突状细胞，但由于缺乏NIPC的明确表型，进展受到一定阻碍。NIPC与浆细胞样树突状细胞（PDC）是相同的。PDC被认为不仅作为专业IPC而且作为先天免疫和适应性免疫之间的重要联系是重要的。HIV感染中IFN-α产生的缺陷是由于循环PDC数量的减少以及存在的那些细胞的功能障碍。目前的研究有五个具体目标;前三个涉及PDC的基础生物学研究，后两个应用已经了解的PDC的功能，以了解它们如何在HIV感染患者中变得缺乏。外周血PDC表达非常高的组成水平的转录因子IRF-7。这些观察将被扩展以评估IRF-7在不同解剖部位的PDC中的表达和功能，并确定IRF-7与IRF-3和IRF- 5在这些细胞中的作用。PDC表面上受体的交联导致其产生IFN-α的能力下调，这一现象也可能在HIV感染患者中具有生理相关性。提出研究以理解这种下调的机制，并确定PDC执行的其他功能（例如TNF-α和趋化因子的产生）是否同样受到受体交联的影响。通过PDC产生IFN-α不需要用病毒感染细胞;相反，通过内吞作用摄取物质似乎触发IFN-α的产生。使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。在研究中，以更好地了解艾滋病毒感染患者的PDC缺陷的机制，将进行研究，以确定PDC是否感染艾滋病毒在体内，以及他们是否从血液中贩运到组织中的网站。最后，提出研究以评估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细胞的活化以及评估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.