Defining the Pathogenesis of Immune Deficiency in Chronic HIV Infection

该项目申请由克利夫兰免疫病理学联盟（CLIC）的成员提交，该联盟是一组代表美国和加拿大10个学术和研究机构的研究人员，他们从事了三年多的协调研究工作，旨在揭示HIV感染导致进行性免疫缺陷的机制。这组经验丰富，优秀的研究人员利用互补的研究技能和资源，并提出了一个跨学科的计划，包括由两个核心协调和支持的4个项目：行政核心，负责项目和标本采集核心的总体协调和管理，Alan Landay，PI，负责确保肠道和淋巴结临床标本的持续供应，以支持项目研究人员。这些项目包括一系列相互作用的研究平台，从基础实验室研究到实验动物模型再到转化项目，每个项目都旨在探索免疫激活驱动慢性HIV感染中CD 4 + T细胞耗竭和功能障碍的决定因素和机制。项目#1：旁观者激活驱动慢性HIV感染中的T细胞损失-PI：Michael M.莱德曼，医学博士，斯科特·F Sieg博士- 病例，将检验以下假设：在慢性HIV感染中，次级淋巴组织中微生物TLR配体和常见γ链细胞因子的全身水平增加驱动中枢记忆T细胞活化和周转。项目#2：HIV感染中肠道屏障功能的丧失- Alan Levine博士病例，将检查HIV感染中肠粘膜的完整性，以记录微生物产物通过受损肠道的增强易位的机制细节，我们提出这有助于慢性HIV感染中细胞丢失的发病机制。项目#3：SIV感染的非人灵长类动物的免疫激活和艾滋病发病机制- Guido Silvestri，医学博士，宾夕法尼亚大学，将尝试通过激活先天免疫系统在非致病性SIV感染的白眉猴中诱导疾病，并将测试阻断先天免疫激活是否会减弱受感染恒河猴的疾病发病机制。项目#4：免疫激活促进慢性HIV感染中的PD 1表达和免疫功能障碍- Rafick Pierre Sekaly博士- 蒙特利尔大学，将通过HIV RNA和TLR 7/8对PDL-1和2表达的相互作用及其对HIV反应性T细胞功能和存活的影响来研究先天免疫系统激活的作用。

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.