Mechanisms of HIV-associated Gut T Cell Depletion

HIV 相关肠道 T 细胞耗竭的机制

• 批准号: 8836953
• 负责人: Cara C. Wilson
• 金额: $ 47.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836953
• 关键词: AIDS/HIV problem; Accounting; Acute; Address; Apoptosis; Apoptotic; Bacteria; Bacterial Translocation; Biological; Biological Preservation; Blood Circulation; CCR5 gene; CD4 Positive T Lymphocytes; Caspase; Cell Death; Cells; Cessation of life; Characteristics; Chronic; Development; Disease Progression; Enteral; Enterobacteriaceae; Epithelial; Escherichia coli; Event; Exhibits; Exposure to; Frequencies; Gene Expression Profiling; Genetic; Grant; Gut associated lymphoid tissue; HIV; HIV-1; Heterosexuals; Immune; Immune system; Immunologic Factors; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-17; Intestinal Mucosa; Intestines; Knowledge; Label; Lamina Propria; Lead; Life Cycle Stages; Link; Lymphocyte; Maps; Mediating; Microbe; Modeling; Molecular Cloning; Molecular Profiling; Mononuclear; Mucositis; Nature; Necrosis; Pathway interactions; Patients; Persons; Phenotype; Play; Positioning Attribute; Process; Property; Publishing; Research; Role; SIV; Staging; System; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Tissues; Transcript; Uncertainty; Viral; Virus; base; cell killing; cell type; cytokine; immune activation; insight; killings; microbial; novel; pathogen; prevent; public health relevance; transmission process

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.

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。尽管对该主题进行了大量已发表的研究，但大多数之前的CD 4 + T细胞杀伤研究都使用了嗜X4的HIV-1毒株和细胞类型，这些毒株和细胞类型与了解粘膜区室中的CD 4 + T细胞消耗不直接相关。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细胞消耗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。