Defining the Pathogenesis of Immune Deficiency in Chronic HIV Infection

定义慢性 HIV 感染免疫缺陷的发病机制

• 批准号: 8115015
• 负责人: MICHAEL MARCEL LEDERMAN
• 金额: $ 194.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115015
• 关键词: Defining; Pathogenesis; Immune; Deficiency; Chronic

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.

描述（由申请人提供）：该计划项目申请由克利夫兰免疫发病机制联盟 (CLIC) 的成员提交，该联盟由代表美国和加拿大 10 个学术和研究机构的研究人员组成，他们三年多来一直致力于协调研究工作，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、杰出的研究人员利用互补的研究技能和资源，提出了一个跨学科计划，包括 4 个项目，由两个核心协调和支持：行政核心，负责该计划的整体协调和管理；标本采集核心，艾伦·兰迪 (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，每个平台都旨在探索慢性 HIV 感染中免疫激活驱动 CD4+ T 细胞耗竭和功能障碍的决定因素和机制。项目#1：旁观者激活导致慢性 HIV 感染中 T 细胞损失 - PI：Michael M. Lederman，医学博士、Scott F. Sieg 博士。 - Case，将检验以下假设：次级淋巴组织中微生物 TLR 配体和常见伽马链细胞因子的全身水平增加可驱动慢性 HIV 感染中的中枢记忆 T 细胞激活和周转。项目 #2：HIV 感染导致肠道屏障功能丧失 - Alan Levine 博士凯斯将检查 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增强易位的机制细节，我们认为这有助于慢性 HIV 感染中细胞损失的发病机制。项目#3：感染 SIV 的非人类灵长类动物的免疫激活和艾滋病发病机制 - 宾夕法尼亚大学医学博士 Guido Silvestri 将尝试通过激活先天免疫系统来诱导乌白眉猴的非致病性 SIV 感染疾病，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 PD1 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 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，以及它们对 HIV 反应性 T 细胞的功能和存活的影响。