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.

肠和脑通过肠-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 肠道CD 4 + T细胞和巨噬细胞，因为这些部位表达大量表达CCR 5的活化 CD 4 + T细胞。在HIV/SIV感染期间靶向肠道导致肠道CD 4 + 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性疾病。 activation.整合素α4β7在一些CD 4 + T细胞表面上以高水平存在，并参与肠道免疫。 手机交易一些HIV/SIV毒株能够与α4β 7 hi CD 4 + T细胞上的α4β7结合，使细胞更多地 易受感染胃肠道内表达α4β 7 hi的CD 4 + 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相关， 疾病进展速度加快。静脉注射（i. v.）给予抗α4β7单克隆抗体， 当RM用i.v、i.r或IVAG攻击时，恒河猴保护GALT免受感染 航线这种保护作用是通过提高外周血幼稚、中枢记忆水平 CD 4 + T细胞。值得注意的是，抗α4β7单克隆抗体对ART治疗的SIV感染的RM的给药导致 即使在ART治疗后，血浆/GALT病毒载量也受到高度显著、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。以来 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 减少胃肠道组织中的病毒储库，从而间接减少CNS病毒储库。到 为了验证这一假设，将在急性感染期间沿着给猕猴组施用抗α4β7抗体。 联合抗逆转录病毒疗法（cART）。来自血浆、CSF和CNS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， 炎症标志物（Aim 1）。此外，敏感的储库测定，如病毒生长测定（VOA）， 和高灵敏度达特/rev诱导有限稀释试验（TILDA）将用于测量 巨噬细胞/小胶质细胞（Aim 2），其从Aim 1中的动物的脑中纯化，其将鉴定巨噬细胞/小胶质细胞（Aim 2）。 在CNS中建立病毒储库。