Cytomegalovirus (CMV), the gut barrier and immune dysfunction in HIV

巨细胞病毒 (CMV)、HIV 的肠道屏障和免疫功能障碍

• 批准号: 10177602
• 负责人: PETER W HUNT
• 金额: $ 77.27万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10177602
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Address; Ancillary Study; Antigen Presentation; Biological Markers; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical Trials; Colorectal; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; DNA; Defect; Dendritic Cells; Disease; Epitopes; Failure; Functional disorder; Funding; Gap Junctions; Gastrointestinal tract structure; General Population; Gut Mucosa; HIV; HIV Infections; Homing; Immune System Diseases; Individual; Infection; Lead; Life Expectancy; Macaca mulatta; Measures; Mediating; Modeling; Modified Vaccinia Virus Ankara; Mucous Membrane; Parents; Participant; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Plasma; Recording of previous events; Role; Series; Site; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Tissues; Tretinoin; United States National Institutes of Health; Vaccination; Vaccine Therapy; Vaccines; antigen-specific T cells; antiretroviral therapy; base; co-infection; cohort; exhaustion; gastrointestinal; gastrointestinal epithelium; immune activation; imprint; improved; improved outcome; in vivo; intestinal barrier; microbial; mortality; peripheral blood; response; senescence; trafficking; vaccination strategy; vector vaccine

ABSTRACT. This REVISED collaborative R01 application addresses the impact of cytomegalovirus (CMV) on the gastrointestinal mucosa in chronic HIV infection. We hypothesize that CMV infection contributes to the intestinal barrier dysfunction and consequent immune activation that persist in chronic HIV infection despite suppressive antiretroviral therapy (ART). In Aim 1, based on strong preliminary studies, we hypothesize that CMV persistence in the gastrointestinal tract results in part from the failure of CMV-specific CD8+ T-cells to localize to this tissue. To determine the breadth and functionality of CMV-specific T-cell responses in gut, we will measure responses in colorectal tissue from participants in the SCOPE cohort at UCSF. To determine the effects of CMV infection on antigen presentation in gut, we will employ the rhesus macaque model of CMV (RhCMV) and SIVmac to study interactions between mucosal dendritic cells (DC) and T-cells ex vivo. In Aim 2, we will leverage an externally-funded clinical trial (AIDS Clinical Trials Group Study #A5383) to directly test the hypothesis that asymptomatic CMV replication contributes significantly to microbial translocation in treated HIV disease. We will determine the effects of suppression of CMV replication with letermovir on systemic biomarkers of microbial translocation as well as immune activation and gut barrier integrity assessed directly in gut mucosal tissues. Taken together, these studies will determine the contributions of CMV to immune activation in HIV disease, and the mechanistic bases for these effects. Aim 3 leverages a second ACTG study (#A5355) to determine whether a modified vaccine Ankara (MVA)-based CMV vaccine can increase systemic and/or gut- homing and mucosal CMV-specific T-cell responses in treated HIV infection. Failure of a therapeutic anti-CMV vaccine to elicit gut-homing CMV-specific T-cell responses and to reduce mucosal CMV shedding may compromise its ability to reduce systemic immune activation in treated HIV infection and would highlight the need for optimization of vaccination strategies to improve mucosal responses. (Note: Aims 2 and 3 do not meet the NIH definition of a clinical trial; the ancillary studies in these Aims only add additional measures to pre-existing trials).

抽象的。此修订的协作R01应用程序涉及巨细胞病毒（CMV）对 慢性HIV感染中的胃肠道粘膜。我们假设CMV感染有助于 尽管 抑制性抗逆转录病毒疗法（ART）。在AIM 1中，基于强大的初步研究，我们假设 胃肠道中的CMV持久性部分是由于CMV特异性CD8+ T细胞失败至 定位于该组织。为了确定肠道中CMV特异性T细胞响应的广度和功能，我们将 测量UCSF范围队列参与者的结直肠组织的反应。确定效果 CMV感染在肠道中的抗原表现中，我们将采用CMV的恒河猴模型（RHCMV） SIVMAC研究粘膜树突状细胞（DC）和T细胞离体之间的相互作用。在AIM 2中，我们将 利用外部资助的临床试验（AIDS临床试验组研究＃A5383）直接测试 假设无症状的CMV复制对治疗的HIV中的微生物易位显着贡献 疾病。我们将确定使用Letermovir抑制CMV复制对全身生物标志物的影响 直接在肠粘膜中评估的微生物易位以及免疫激活和肠道屏障完整性 组织。综上所述，这些研究将确定CMV对HIV中免疫激活的贡献 疾病以及这些作用的机械基础。目标3利用第二个ACTG研究（＃A5355） 确定基于修改的疫苗Ankara（MVA）基于CMV疫苗是否可以增加全身和/或肠道疫苗 治疗的HIV感染中的归巢和粘膜CMV特异性T细胞反应。治疗性抗CMV的失败 引起肠道毒素CMV特异性T细胞反应并减少粘膜CMV脱落的疫苗可能 损害其减少治疗的HIV感染中全身免疫激活的能力，并强调需求 用于优化疫苗接种策略以改善粘膜反应。 （注意：目标2和3不符合 NIH的临床试验定义；这些目标中的辅助研究仅增加了其他措施以预先存在 试验）。