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Mechanisms of HIV-associated Gut T Cell Depletion

Mechanisms of HIV-associated Gut T Cell Depletion
HIV 相关肠道 T 细胞耗竭的机制
批准号:
8602640
负责人:
Cara C. Wilson
金额:
$42.8万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-05-15 至 2018-04-30

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中文摘要
翻译
描述(由申请方提供):在感染的早期阶段,肠道相关淋巴组织(GALT)中的HIV-1复制导致粘膜效应CD 4 + T细胞大量耗竭,特别是产生IL-17的CD 4 + T细胞(Th 17)。Th 17细胞的消耗导致细菌从管腔移位到固有层(LP)中,随后移位到循环中,这是与增加的免疫激活和炎症相关的过程。因此,了解HIV-1如何诱导GALT CD 4 + T细胞死亡可能是预防HIV- 1感染的炎症后遗症的关键。然而,HIV-1杀死CD 4 + T细胞的机制仍然是基础HIV/AIDS研究中最关键的未回答的问题之一。尽管已发表了大量关于该主题的研究,但大多数先前的CD 4 + T细胞杀伤研究使用了X4嗜性HIV-1毒株和细胞类型,这些毒株和细胞类型与理解粘膜隔室中的CD 4 + T细胞耗竭不直接相关。为了解决这个问题,我们最近开发了一种新的实验系统,使用原代肠粘膜细胞体外模拟R5嗜性HIV-1,微生物物种和LP CD 4 + Th细胞亚群之间的相互作用。因此,我们的合作团队在解决HIV-1粘膜免疫发病机制中的以下关键知识缺口方面处于独特的地位:1。R5-tropic HIV-1如何导致GALT CD 4 + T细胞死亡? 2.易位的肠道细菌如何影响HIV介导的GALT CD 4 + T细胞杀伤? 3.哪些病毒决定因素介导了传播/创始HIV-1毒株的GALT CD 4 + T死亡?使用我们的动态离体LP感染模型,我们提出了三个具体的目标来解决这些重要的问题。在目标1中,我们将利用不同标记的HIV-1感染和未感染的细胞,通过抵消半胱天冬酶活性,在其生命周期的离散步骤抑制HIV-1,并使用非偏倚基因表达谱,研究PCD途径在HIV-1介导的CD 4 + T细胞死亡中的作用。在目标2中,我们将确定代表性肠道细菌物种单独和组合对HIV-1介导的LP CD 4 + T细胞死亡的生物学影响,并确定影响CD 4 + T细胞耗竭的细菌的免疫调节特性。在目标3中,我们将记录一组40个传播/创始者和慢性HIV-1亚型B和C感染性分子克隆的复制和杀伤特征,以确定导致LP CD 4 + T细胞死亡的病毒特征。这些研究的结果可能最终提供对可以靶向保护或恢复HIV感染患者粘膜免疫系统完整性的途径的深入了解,从而限制全身炎症及其下游后果。
英文摘要
DESCRIPTION (provided by applicant): HIV-1 replication in gut-associated lymphoid tissue (GALT) in the early stages of infection results in massive depletion of mucosal effector CD4+ T cells, in particular IL-17-producing CD4+ T cells (Th17). Depletion of Th17 cells leads to bacterial translocation from the lumen into the lamina propria (LP) and subsequently the circulation, a process associated with increased immune activation and inflammation. Thus, understanding how HIV-1 induces GALT CD4+ T cell death may be key to preventing the inflammatory sequelae of HIV- 1 infection. However, the mechanism by which HIV-1 kills CD4+ T cells remains one of the most critical unanswered questions in basic HIV/AIDS research. Despite extensive published studies on the subject, most prior CD4+ T cell killing studies utilized X4-tropic HIV-1 strains and cell types that are not directly relevant to understanding CD4+ T cell depletion in mucosal compartments. To address this issue, we recently developed a novel experimental system to model the interactions between R5-tropic HIV-1, microbial species and LP CD4+ Th cell subsets ex vivo using primary intestinal mucosal cells. Thus, our collaborative team is in a unique position to address the following critical knowledge gaps in HIV-1 mucosal immunopathogenesis: 1. How does R5-tropic HIV-1 cause GALT CD4+ T cell death? 2. How do translocating enteric bacteria influence HIV-mediated GALT CD4+ T cell killing? 3. Which viral determinants mediate GALT CD4+ T death by transmitted/founder HIV-1 strains? Using our dynamic ex vivo LP infection model, we propose three specific aims to address these important questions. In Aim 1, we will utilize differentially-labeled HIV-1 infected and uninfected cells to investigate the role of PCD pathways in HIV-1 mediated CD4+ T cell death by counteracting caspase activity, inhibiting HIV-1 at discrete steps in its life cycle, and using non-biased gene expression profiling. In Aim 2, we will determine the biological impact of representative gut bacterial species individually, and in combination, on HIV-1 mediated LP CD4+ T cell death and identify the immunomodulatory properties of bacteria that influence CD4+ T cell depletion. In Aim 3, we will document the replication and killing characteristics of a panel of 40 Transmitted/Founder and chronic HIV-1 Subtype B and C infectious molecular clones, to define the viral characteristics responsible for LP CD4+ T cell death. The results of these studies may ultimately provide insight into pathways that can be targeted to preserve or restore the integrity of the mucosal immune system in HIV- infected patients and thereby limit systemic inflammation and its downstream consequences.
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Medical Scientist Training Program
  • 批准号:
    10625798
  • 项目类别:
  • 资助金额:
    $104.5万
  • 财政年份:
    2023
  • 负责人:
    Cara C. Wilson
  • 依托单位:
Dysregulated gut-microbe CD4 T cell interactions with Aging
  • 批准号:
    9895280
  • 项目类别:
  • 资助金额:
    $23.33万
  • 财政年份:
    2019
  • 负责人:
    Cara C. Wilson
  • 依托单位:
Dysregulated gut-microbe CD4 T cell interactions with Aging
  • 批准号:
    10023254
  • 项目类别:
  • 资助金额:
    $19.44万
  • 财政年份:
    2019
  • 负责人:
    Cara C. Wilson
  • 依托单位:
Mechanisms of HIV-associated Gut T Cell Depletion
  • 批准号:
    9060866
  • 项目类别:
  • 资助金额:
    $45.49万
  • 财政年份:
    2013
  • 负责人:
    Cara C. Wilson
  • 依托单位:
海外基金