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）：该计划项目申请是由克利夫兰免疫病变联盟（CLIC）的成员提交的一组研究人员，代表了美国和加拿大的10家学术和研究机构，他们从事了三年以上的研究工作，该研究旨在揭示HIV HIV Infictight in Callessive Sefune in Callessive Invefiction Sefune Sefection Sefune Sefune sealtive Insvience in Callistive Insune sealtive farne sealige seftive hivefection。 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.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，每个项目旨在探索决定因素和机制，免疫激活驱动CD4+ T细胞的耗竭和慢性HIV感染功能障碍。项目＃1：旁观者激活驱动慢性艾滋病毒感染中的T细胞损失-PIS：Michael M. Lederman，M.D。，Scott F. Sieg Ph.D. - 案例将检验以下假设：在次级淋巴组织中，微生物TLR配体的全身水平和常见的γ链细胞因子驱动中心记忆T细胞激活和慢性HIV感染中的周转率。项目＃2：HIV感染中肠道屏障功能的丧失-Alan Levine，Ph.D。案例，将检查肠道粘膜在HIV感染中的完整性，以记录通过肠道受损的肠道增强微生物产物易位的机械细节，我们提出的这有助于慢性HIV感染中细胞丧失的发病机理。项目＃3：宾夕法尼亚州大学的SIV感染的非人类灵长类动物的免疫激活和辅助发病机制 - Guido Silvestri，M.D.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 Ph.D. - 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的作用，对PDL-1和2的表达及其对HIV反应性T细胞功能和存活的影响。