Defining the Pathogenesis of Immune Deficiency in Chronic HIV Infection

描述(由申请人提供)：本计划项目申请由克利夫兰免疫病理联盟(CLIC)的成员提交，CLIC是一个由代表美国和加拿大的10个学术和研究机构的研究人员组成的小组，他们三年多来一直致力于一项旨在揭示艾滋病毒感染导致进行性免疫缺陷的机制的协调研究工作。这组经验丰富、杰出的研究人员利用互补的研究技能和资源，提出了一个由两个核心协调和支持的跨学科计划：行政核心，负责计划的整体协调和管理，以及标本获取核心，负责确保持续供应肠道和淋巴结的临床标本，以支持项目研究人员。这些项目包括一系列互动研究平台，从基础实验室研究到实验动物模型再到翻译项目，每个平台都旨在探索免疫激活导致慢性HIV感染中CD4+T细胞耗尽和功能障碍的决定因素和机制。项目1：旁观者激活导致慢性HIV感染中T细胞的损失-PI：Michael M.Lederman，M.D.，Scott F.Sieg Ph.D.-Case，将测试以下假设：在慢性HIV感染中，系统中微生物TLR配体和次级淋巴组织中常见的伽马链细胞因子水平的增加推动中央记忆T细胞的激活和更新。项目2：HIV感染中肠道屏障功能的丧失-Alan Levine博士案例，他将研究HIV感染中肠道粘膜的完整性，以记录下微生物产物通过受损肠道促进转运的机制细节，我们认为这有助于慢性HIV感染中细胞丢失的发病机制。项目3：免疫激活与感染SIV的非人类灵长类动物的艾滋病发病机制-宾夕法尼亚大学医学博士Guido Silvestri将尝试通过激活固有免疫系统来诱导非致病性SIV感染烟尘猴的疾病，并将测试阻断先天性免疫激活是否会减轻受感染的恒河猴的疾病发病。项目4：免疫激活促进慢性HIV感染中PD1的表达和免疫功能障碍-蒙特利尔大学Rafick Pierre Sekaly Ph.D.将通过HIV RNAs和TLR7/8之间的相互作用来研究先天免疫系统激活对PDL-1和2表达的作用及其对HIV反应T细胞功能和生存的影响。

DESCRIPTION (provided by applicant): This program project application is submitted by the members of the Cleveland Immunopathogenesis Consortium (CLIC) a group of investigators representing 10 academic and research institutions in the United States and Canada who have engaged for more than three years in a coordinated research effort aimed at unraveling the mechanisms whereby HIV infection results in progressive immune deficiency. This group of experienced, outstanding investigators capitalizes on complementary research skills and resources and proposes an interdisciplinary program comprising 4 projects that are coordinated and supported by two cores: Administrative Core, charged with overall coordination and administration of the program and Specimen Acquisition Core, Alan Landay, PI, charged with assuring a sustained supply of clinical specimens of gut and lymph nodes to support project investigators. The projects comprise a series of interacting research platforms from basic laboratory research to experimental animal models to translational projects, each designed to explore the determinants and mechanisms whereby immune activation drives CD4+ T cell depletion and dysfunction in chronic HIV infection. Project #1: Bystander activation drives T cell losses in chronic HIV infection - PIs: Michael M. Lederman, M.D., Scott F. Sieg Ph.D. - Case, will test the hypothesis that increased systemic levels of microbial TLR ligands and common gamma chain cytokines in secondary lymphoid tissues drive central memory T cell activation and turnover in chronic HIV infection. Project #2: Loss of intestinal barrier function in HIV infection - Alan Levine, Ph.D. Case, will examine the integrity of the intestinal mucosa in HIV infection to document the mechanistic details underlying the enhanced translocation of microbial products through the damaged gut that we propose contributes to the pathogenesis of cell loss in chronic HIV infection. Project #3: Immune activation and AIDS pathogenesis in SIV-infected non-human primates - Guido Silvestri, M.D., Univ of Pennsylvania, will attempt to induce disease in non-pathogenic SIV infection of sooty mangabeys by activation of the innate immune system and will test whether blocking innate immune activation will attenuate disease pathogenesis in infected rhesus macaques. Project #4: Immune activation promotes PD1 expression and immune dysfunction in chronic HIV infection - Rafick Pierre Sekaly Ph.D. - Univ of Montreal, will examine the role of innate immune system activation through the interaction between HIV RNAs and TLR7/8 on the expression of PDL-1 and 2 and their effects on the function and survival of HIV reactive T cells.