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: 10578682
• 负责人: PETER W HUNT
• 金额: $ 77.05万
• 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/10578682
• 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; Life Expectancy; Macaca mulatta; Measures; Mediating; Modeling; Modified Vaccinia Virus Ankara; Mucous Membrane; Parents; Participant; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Plasma; Prediction of Response to Therapy; 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).

摘要。本修订后的协作R01申请解决了巨细胞病毒（CMV）对细胞的影响