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: 7666054
• 负责人: MICHAEL MARCEL LEDERMAN
• 金额: $ 238.95万
• 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/7666054
• 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. PROJECT 1: Bystander activation drives T cell losses in chronic HIV infection (Michael Lederman) PROJECT 1 DESCRIPTION (provided by applicant): Recent data from our collaborative group provide background for a new model of HIV pathogenesis that will be tested here. In this model, turnover of central memory (CM) CD4+ T cells is central to progressive cell losses of HIV infection. We propose that this is driven by interplay between indirect effects of HIV replication on the cytokine environment of secondary lymphoid tissues and in situ exposure to microbial TLR ligands translocated from the damaged gut. HIV replication is necessary but not sufficient to promote T cell turnover; microbial TLR ligands provide additional signals via two distinct mechanisms. First, they promote enhanced non-specific retention of effector CD8+ T cells in secondary lymphoid tissues by increasing expression of the C-type lectin CD69 that interferes with surface expression of sphingosine-1 phosphate receptors needed to permit exit of activated cells from lymph nodes. Sequestration of effector cells intensifies the cytokine "storm" in these tissues that results in explosive levels of common gamma chain receptor cytokines IL-2 and IL-15 that we have quantified at these sites. TLR ligands also activate CM T cells to lose characteristic resistance to death signals a resistance that is due to FOXO3a phosphorylation and inactivation. This results in heightened turnover and selective death of CM CD4+ T cells that drives the immune deficiency of HIV infection. Our aims are: 1) To characterize the intercellular interactions and mechanisms whereby selected TLR ligands and common gamma chain receptor cytokines promote activation of central memory CD4+ and CD8+ T cells. This will be achieved by detailing the specific ARC requirements for T cell activation, by exploring selected gene expression patterns for signals characteristic of cell cycle progression, apoptosis and survival and to use these results to identify the pathways that render CM T cells in HIV infection more susceptible to death signals. 2) To establish in vitro models for bystander T cell activation and sequestration after exposure to TLR ligands and common gamma chain receptor cytokines in secondary lymphoid tissues. This will be accomplished first by defining the model using peripheral blood mononuclear cells in suspension and then confirming the model in lymph node histoculture experiments. 3) To identify the proximate causes of immune activation in chronic HIV infection. We will determine the levels of selected microbial TLR agonists, HIV RNA and bacterial PGN, LPS and DNA in the plasma of chronically HIV infected persons. Based upon the results of SpAim 1 experiments, we will develop a panel of flow based reagents that will characterize the signatures of bystander T cell activation that will be applied to ex vivo analyses of blood, lymph node and gut lymphocytes 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。 项目1：慢性HIV感染中旁观者的激活导致T细胞丢失(Michael Lederman) 项目1描述(由申请人提供)：来自我们合作小组的最新数据为将在这里测试的艾滋病毒发病机制的新模型提供了背景。在这个模型中，中央记忆(CM)CD4+T细胞的周转是HIV感染进行性细胞损失的核心。我们认为这是由HIV复制对次级淋巴组织细胞因子环境的间接影响和原位暴露于从受损肠道移位的微生物TLR配体之间的相互作用所推动的。HIV复制是必要的，但不足以促进T细胞周转；微生物TLR配体通过两种不同的机制提供额外的信号。首先，它们通过增加C型凝集素CD69的表达来促进效应CD8+T细胞在次级淋巴组织中的非特异性保留，C型凝集素CD69干扰了允许激活细胞从淋巴结中退出所需的鞘氨醇-1磷酸受体的表面表达。效应细胞的隔离加剧了这些组织中的细胞因子风暴，导致常见伽马链受体细胞因子IL-2和IL-15的爆炸性水平，我们已经在这些部位进行了量化。TLR配体还激活CM T细胞，使其失去对死亡信号的特有抵抗，这种抵抗是由于FOXO3a磷酸化和失活造成的。这导致CM CD4+T细胞的高周转率和选择性死亡，从而导致艾滋病毒感染的免疫缺陷。我们的目标是：1)研究特定的TLR配体和常见的伽马链受体细胞因子促进中枢记忆的CD4+和CD8+T细胞活化的细胞间相互作用和机制。这将通过详细说明T细胞激活的特定ARC要求，通过探索细胞周期进展、凋亡和生存信号特征的选定基因表达模式来实现，并利用这些结果来确定使HIV感染中的CM T细胞更容易受到死亡信号影响的途径。2)建立TLR配体和常见的γ-链受体细胞因子作用于次级淋巴组织后旁观者T细胞活化和隔离的体外模型。这将首先通过定义使用悬液中的外周血单核细胞的模型，然后在淋巴组织培养实验中确认该模型来实现。3)找出慢性HIV感染中免疫激活的直接原因。我们将测定选定的微生物TLR激动剂、HIV RNA和细菌PGN、LPS和DNA在慢性HIV感染者血浆中的水平。基于SpAim 1实验的结果，我们将开发一组基于Flow的试剂，该试剂将表征旁观者T细胞激活的特征，并将应用于慢性HIV感染的血液、淋巴和肠道淋巴细胞的体外分析。