Targeting gut-brain axis to eliminate CNS reservoirs

瞄准肠脑轴消除中枢神经系统储库

• 批准号: 9350887
• 负责人: Siddappa N Byrareddy
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350887
• 关键词: Acute; Address; Affect; Animals; Anti-Retroviral Agents; Antibodies; Autopsy; Binding; Biological Assay; Brain; Brain Pathology; CCR5 gene; CCR6 gene; CD4 Positive T Lymphocytes; Cells; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Crohn' s disease; Data; Development; Diarrhea; Disease; Disease Progression; Endocrine; Enzymes; Epithelial; Frequencies; Functional disorder; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Homing; Human; Immune; Immune signaling; Immunotherapy; Impairment; Infection; Inflammation; Integrin alpha4; Integrins; Interruption; Intravenous; Kynurenine; Laboratories; Lead; Leukocyte Trafficking; Lymphoid Tissue; Macaca; Macaca mulatta; Malabsorption Syndromes; Malnutrition; Measurement; Measures; Memory Loss; Mental Depression; Microglia; Modeling; Monkeys; Monoclonal Antibodies; Mucous Membrane; N' -formylkynurenine; Names; Neuraxis; Nutrient; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Primates; Process; Progressive Multifocal Leukoencephalopathy; Public Health; Research; Role; Route; SIV; Series; Signal Transduction; Site; Standardization; Surface; System; T-Lymphocyte; Testing; Thinking; Tight Junctions; Time; Tissues; Tryptophan; Tryptophan 2,3 Dioxygenase; Ulcerative Colitis; United States National Institutes of Health; Up-Regulation; Vagina; Vascular Cell Adhesion Molecule-1; Viral; Viral Load result; Viral reservoir; Virus; antiretroviral therapy; cell type; clinical efficacy; design; experience; gastrointestinal; gastrointestinal system; immune activation; in vivo; inflammatory marker; integrin alpha4beta7; macrophage; memory CD4 T lymphocyte; microbial; monocyte; motor impairment; mucosal site; natalizumab; neurotransmission; new therapeutic target; peripheral blood; relating to nervous system; trafficking; virology; wasting

The gut and brain are connected via the gut-brain axis (GBA), wherein the neural and immunological signals are transmitted between the central nervous system (CNS) and the gut. During acute infection, HIV/SIV targets gut CD4+ T cells and macrophages because these sites express high numbers CCR5-expressing activated CD4+ T cells. Targeting of the gut during HIV/SIV infection results in severe depletion of gut CD4+ T cells and ensuing mucosal tissue dysfunction resulting in leaky gut, microbial translocation and chronic immune activation. The integrin α4β7 is found at high levels on the surface of some CD4+ T cells and is involved in gut- cell trafficking. Some strains of HIV/SIV are able to bind to α4β7 on α4β7hi CD4+ T cells making the cells more susceptible to infection. Increased frequency of α4β7hi-expressing CD4+ T cells within the gastrointestinal associated lymphoid tissues (GALT) at the time of infection appears to correlate with increased viral loads and enhanced rate of disease progression. Intravenous (i.v.) administration of anti-α4β7 monoclonal antibody to rhesus macaques protected the GALT from infection when RMs were challenged with either i.v, i.r or IVAG routes. The protection was established by both enhancing the levels of peripheral blood naive, central memory CD4+ T cells. Remarkably, administration of anti-α4β7 mAb to ART-treated SIV-infected RMs resulted in a highly significant, unprecedented suppression of plasma/GALT viral loads even after ART treatment interruption. These studies, taken together, highlight the role of α4β7 in HIV pathogenesis and treatment. Since the gut and brain are connected via the GBA, we hypothesize that controlling viral loads in the GALT will lead to diminished viral reservoirs in gastrointestinal tissues, which indirectly reduces the CNS viral reservoir. To test this hypothesis, groups of macaques will be administrated anti-α4β7 antibody during acute infection along with combination anti-retroviral therapy ART (cART). The viral loads from plasma, CSF and CNS tissue (at necropsy) will be assessed including the measurement of phenotypic characteristics of immune cells and inflammatory markers (Aim 1). Furthermore, sensitive reservoir assays such as viral outgrowth assay (VOA) and highly sensitive Tat/rev Induced Limiting Dilution Assay (TILDA) will be used to measure inducible virus in macrophages/microglia (Aim 2) purified from the brains of the animals in Aim 1, which will identify the establishment of the viral reservoir in the CNS.

肠道和大脑通过肠脑轴（GBA）连接，其中神经和免疫信号 在中枢神经系统（CNS）和肠道之间传播。在急性感染期间，HIV/SIV 的目标是 肠道 CD4+ T 细胞和巨噬细胞，因为这些位点表达大量表达 CCR5 的激活细胞 CD4+ T 细胞。 HIV/SIV 感染期间以肠道为目标会导致肠道 CD4+ T 细胞严重耗竭， 随后的粘膜组织功能障碍导致肠漏、微生物易位和慢性免疫 激活。整合素 α4β7 在一些 CD4+ T 细胞的表面上发现高水平，并且参与肠道- 细胞贩运。某些 HIV/SIV 毒株能够与 α4β7hi CD4+ T 细胞上的 α4β7 结合，从而使细胞更 容易受到感染。胃肠道内表达 α4β7hi 的 CD4+ T 细胞频率增加 感染时的相关淋巴组织（GALT）似乎与病毒载量增加和 疾病进展速度加快。静脉注射（i.v.）抗α4β7单克隆抗体 当 RM 受到静脉注射、静脉注射或 IVAG 攻击时，恒河猴保护 GALT 免受感染 路线。这种保护是通过增强外周血幼稚、中枢记忆的水平来建立的。 CD4+ T 细胞。值得注意的是，向经 ART 处理的 SIV 感染 RM 施用抗 α4β7 mAb 导致 即使在 ART 治疗后，血浆/GALT 病毒载量也受到高度显着、前所未有的抑制 中断。这些研究共同强调了 α4β7 在 HIV 发病机制和治疗中的作用。自从 肠道和大脑通过 GBA 连接，我们假设控制 GALT 中的病毒载量将导致 胃肠道组织中的病毒库减少，从而间接减少了中枢神经系统病毒库。到 为了检验这一假设，在急性感染期间，猕猴群将被注射抗 α4β7 抗体， 联合抗逆转录病毒疗法 ART (cART)。来自血浆、脑脊液和中枢神经系统组织的病毒载量（在 尸检）将进行评估，包括测量免疫细胞的表型特征和 炎症标志物（目标 1）。此外，敏感的储存库检测，例如病毒生长检测 (VOA) 高度灵敏的 Tat/rev 诱导限制稀释测定 (TILDA) 将用于测量诱导病毒 从目标 1 中动物的大脑中纯化出巨噬细胞/小胶质细胞（目标 2），这将识别 在中枢神经系统中建立病毒库。