Loss of Intestinal Barrier Function in HIV infection

HIV 感染导致肠道屏障功能丧失

• 批准号: 8115010
• 负责人: Alan David Levine
• 金额: $ 34.51万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8115010
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adherens Junction; Affect; Agonist; Anatomy; Antiviral Agents; Antiviral Therapy; Apical; Appearance; Bacterial DNA; Biochemical; Biological Assay; Biology of HIV Infection; Biopsy; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Cell Death; Cell Fractionation; Cercocebus atys; Cessation of life; Chronic; Clinical; Collaborations; Colon; Complex; DNA; Data; Defect; Diagnostic; Disease; Disease Progression; Distal part of ileum; Doctor of Medicine; Electron Microscopy; Elements; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Failure; Foundations; Functional disorder; Gastrointestinal tract structure; Gene Expression; Gene Expression Microarray Analysis; Genetic; Genus Cola; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Homeostasis; IgA Deficiency; Immune; Immune System and Related Disorders; Immune response; Immunity; Immunoblotting; Immunochemistry; Immunoglobulin A; Immunohistochemistry; Immunologic Deficiency Syndromes; Immunologics; Incidence; Indium; Individual; Infection; Intestinal Mucosa; Intestines; Kinetics; Lamina Propria; Lasers; Ligands; Link; Lipopolysaccharides; Location; MAP3K7 gene; Macaca mulatta; Measurement; Measures; Microscopy; Modeling; Molecular; Molecular Biology; Movement; Mucous Membrane; Oligosaccharides; Pathogenesis; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Peptidoglycan; Permeability; Phase; Physiological; Plasma; Primates; Production; Proteins; RNA; Receptor Signaling; Recovery; Relative (related person); Reporting; Research; Research Personnel; SIV; Serum; Signal Transduction; Small Intestines; Source; Spottings; Stomach; Structure; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Techniques; Testing; Tight Junctions; Toll-like receptors; Transcript; Transmission Electron Microscopy; Viral; Viral Load result; Virus; Virus Diseases; antiretroviral therapy; expectation; gastrointestinal; human IRAK1 protein; immune activation; immune function; immunoregulation; lymph nodes; member; microbial; pathogen; prevent; programs; protein structure; receptor; repaired; research study; response; restoration; trafficking

During the acute phase of an HIV infection, the predominant depletion of CD4+ T cells is localized to the gastrointestinal tract. Furthermore, this substantial depletion does not fully recover with highly active antiviral retroviral therapy. These observations, confirmed in the SIV model of AIDS progression in the Rhesus macaque, indicate that the intestinal immune response is compromised early and suggest that the infected host may be vulnerable to microbial translocation due to (i) increased permeability in the epithelium as well as (ii) loss of mucosal immune function. Consistent with this expectation, our recent data demonstrate increased circulating levels of bacterial lipopolysaccharide, peptidoglycan, and DMA in plasma of HIVinfected individuals. A consequence of increased microbial translocation is systemic innate and adaptive immune activation (to be studied in Projects 1, 3, and 4), which is also incompletely reversed after successful HAART. Therefore, we hypothesize that the chronic systemic immune activation diagnostic of AIDS progression may, in part, be a result of increased paracellular epithelial permeability due to an early loss in intestinal immune defenses. In addition, we will test a secondary hypothesis that increased microbial translocation is a result of a diminished or compromised humoral immune response in the intestine. Since the molecular mechanisms for increased intestinal permeability during HIV infection are unknown, we propose: Aim 1: Determine the location and kinetics of breach incidence in the epithelial barrier by measuring intestinal permeability (IP) directly in HIV-infected patients and SIV-infected Rhesus macaques or Sooty mangabeys. Gastrointestinal permeability will be assessed by measuring the movement of saccharide probes across the epithelium of the stomach, small intestine, and colon in HIV or SIV infections. Aim 2: Evaluate the biochemical and structural integrity of the epithelial apical junctional complex (AJC) in acute and chronic HIV and SIV infection. The composition, assembly, intracellular trafficking, and gene expression of the protein components of the AJC from the terminal ileum and colon of control and HIVor SIV-infected subjects will be compared. Aim 3: Delineate the innate and adaptive immunological dysfunctions in the HIV-infected mucosa that contribute to and are a consequence of microbial translocation. Intestinal biopsies of HIV- or SIV-infected subjects will be probed for the presence of bacterial DNA and others, PAMPs, and for evidence of ongoing toll-like receptor signal transduction, and IgA deficiency. Aim 4: Investigate the degree to which intestinal permeability, apical junctional complex integrity, and PAMP concentration in the lamina propria are reduced, after highly active antiretroviral therapy (HAART) has lessened viral replication. Since HIV DNA is found in the intestinal mucosa even after HAART, we will investigate the degree to which accumulated deficiencies in the epithelium are corrected by HAART.

在 HIV 感染的急性期，CD4+ T 细胞的主要消耗集中在 胃肠道。此外，这种大量的消耗并不能通过高活性抗病毒药物完全恢复。 逆转录病毒疗法。这些观察结果在恒河猴艾滋病进展的 SIV 模型中得到证实 猕猴，表明肠道免疫反应早期就受到损害，并表明受感染的 由于（i）上皮细胞的渗透性增加，宿主可能容易受到微生物易位的影响 (ii) 粘膜免疫功能丧失。与这一预期一致，我们最近的数据表明 HIV感染者血浆中细菌脂多糖、肽聚糖和DMA的循环水平增加 个人。微生物易位增加的结果是系统先天性和适应性的 免疫激活（将在项目 1、3 和 4 中研究），成功后也不完全逆转 高效抗逆转录病毒疗法。因此，我们假设艾滋病的慢性全身免疫激活诊断 进展可能部分是由于早期病变导致细胞旁上皮通透性增加的结果 肠道免疫防御能力丧失。此外，我们将检验一个次要假设，该假设增加了 微生物易位是机体体液免疫反应减弱或受损的结果 肠。由于 HIV 感染期间肠道通透性增加的分子机制是 未知，我们建议： 目标 1：确定上皮细胞中缺口发生的位置和动力学 通过直接测量 HIV 感染者和 SIV 感染恒河猴的肠道通透性 (IP) 来形成屏障 猕猴或乌白眉猴。通过测量运动来评估胃肠道通透性 糖探针穿过 HIV 或 SIV 胃、小肠和结肠上皮 感染。目标 2：评估上皮顶端连接复合体的生化和结构完整性 (AJC) 治疗急性和慢性 HIV 和 SIV 感染。组成、组装、细胞内运输和 对照和 HIVor 末端回肠和结肠 AJC 蛋白质成分的基因表达 将比较感染 SIV 的受试者。目标 3：描绘先天性和适应性免疫学 HIV感染的粘膜功能障碍导致微生物易位，并且是微生物易位的结果。 HIV 或 SIV 感染者的肠道活检将检测是否存在细菌 DNA 和 其他，PAMP，以及持续的 Toll 样受体信号转导和 IgA 缺乏的证据。目标 4： 研究肠道通透性、顶端连接复合体完整性和 PAMP 的程度 高效抗逆转录病毒治疗（HAART）后，固有层中的浓度降低 减少病毒复制。由于即使在HAART后肠粘膜中仍能发现HIV DNA，因此我们将 调查HAART 纠正上皮细胞累积缺陷的程度。