Plasmacytoid Dendritic Cells in HIV Pathogenesis

HIV发病机制中的浆细胞样树突状细胞

• 批准号: 7927712
• 负责人: PATRICIA FITZGERALD-BOCARSLY
• 金额: $ 37.78万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7927712
• 关键词: Address; Affect; Biology; Blood; Cell physiology; Cell surface; Cells; Confocal Microscopy; Dendritic Cells; Disease Progression; Down-Regulation; Drug or chemical Tissue Distribution; Endocytosis; Evaluation; Fibroblasts; Functional disorder; Generations; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Immunity; Infection; Interferon-alpha; Interferons; Label; Learning; Ligands; Link; Myelogenous; Opportunistic Infections; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Predisposition; Production; Regulation; Role; Signal Transduction; Simplexvirus; Site; Staging; Surface; T-Cell Activation; Tissues; Virion; Virus; chemokine; crosslink; cytokine; design; in vivo; peripheral blood; receptor; reconstitution; research study; response; transcription factor; uptake

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.

描述（由申请人提供）：在晚期HIV-1感染患者中观察到由天然IFN产生细胞（NIPC）的干扰素A（IFN-A）的产生。发现这种不足的IFN-A产生与机会性感染的敏感性有关并预测。尽管长期以来是树突状细胞，但由于缺乏NIPC的确定表型，进步受到了阻碍。现已证明NIPC与浆细胞样树突状细胞（PDC）相同。人们认为，PDC不仅很重要，而且很重要，而且是先天性和适应性免疫之间的重要联系。 HIV感染中的IFN-A产生不足是由于循环PDC数量的减少以及存在的这些细胞中的功能障碍。这项当前的研究以五个具体目标进行了组织。前三个涉及对PDC的基本生物学的研究，最后两个应用了有关PDC功能的知识，以了解它们如何在HIV感染患者中缺乏。外周血PDC的转录因子IRF-7表达非常高的本构水平。这些观察结果将扩展以评估IRF-7在不同解剖部位中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，IFN-A的能力也可能在HIV感染的患者中也具有生理意义。提出了研究以了解这种下调的机制，并确定PDC进行的其他功能（例如TNF-A的产生和趋化因子的产生）是否受受体交联的影响。 PDC的产生IFN-A不需要感染病毒。相反，内吞作用对材料的吸收似乎触发了IFN-A的产生。使用荧光标记的感染细胞或病毒和共聚焦显微镜，将确定内吞物质的命运。在更好地了解HIV感染患者PDC缺乏的研究中，将进行研究，以确定PDC是否感染了HIV在体内感染了HIV，以及它们是否将血液从血液中贩运到组织中的部位。最终提出了研究，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以及T细胞的激活以及对这些细胞中IRF-7功能的评估。