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: 10372191
• 负责人: PETER W HUNT
• 金额: $ 76.41万
• 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/10372191
• 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; 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; vaccine 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。此修订版协作 R01 应用程序解决了巨细胞病毒 (CMV) 对 慢性 HIV 感染中的胃肠粘膜。我们推测 CMV 感染有助于 尽管肠道屏障功能障碍和随后的免疫激活在慢性艾滋病毒感染中持续存在 抑制性抗逆转录病毒治疗（ART）。在目标 1 中，基于强有力的初步研究，我们假设 CMV 在胃肠道中持续存在的部分原因是 CMV 特异性 CD8+ T 细胞未能 定位于该组织。为了确定肠道中 CMV 特异性 T 细胞反应的广度和功能，我们将 测量 UCSF SCOPE 队列参与者的结直肠组织反应。确定效果 为了研究 CMV 感染对肠道抗原呈递的影响，我们将采用 CMV 恒河猴模型（RhCMV） 和 SIVmac 用于离体研究粘膜树突状细胞 (DC) 和 T 细胞之间的相互作用。在目标 2 中，我们将 利用外部资助的临床试验（艾滋病临床试验组研究#A5383）直接测试 假设无症状巨细胞病毒复制对治疗艾滋病毒的微生物易位有显着贡献 疾病。我们将确定莱特莫韦抑制 CMV 复制对全身生物标志物的影响 直接在肠道粘膜中评估微生物易位以及免疫激活和肠道屏障完整性 组织。总而言之，这些研究将确定 CMV 对 HIV 免疫激活的贡献 疾病，以及这些影响的机制基础。目标 3 利用第二项 ACTG 研究 (#A5355) 确定基于安卡拉（MVA）的改良疫苗 CMV 疫苗是否可以增加全身和/或肠道 在治疗的 HIV 感染中归巢和粘膜 CMV 特异性 T 细胞反应。抗 CMV 治疗失败 疫苗可引发肠道归巢 CMV 特异性 T 细胞反应并减少粘膜 CMV 脱落 损害其在治疗艾滋病毒感染时减少全身免疫激活的能力，并强调需要 优化疫苗接种策略以改善粘膜反应。 （注：目标2和3不满足 NIH 对临床试验的定义；这些目标中的辅助研究只是在现有的基础上增加了额外的措施 试验）。