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

摘要。本修订版协作R 01应用程序解决了巨细胞病毒（CMV）对 慢性HIV感染者的胃肠道粘膜。我们假设CMV感染有助于 肠屏障功能障碍和随后免疫激活在慢性HIV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在胃肠道中的持续存在部分是由于CMV特异性CD 8 + T细胞未能在胃肠道中表达， 定位于这个组织。为了确定肠道中CMV特异性T细胞应答的广度和功能，我们将 测量来自UCSF SCOPE队列参与者的结直肠组织反应。以确定影响 为探讨巨细胞病毒感染对肠道抗原提呈的影响，我们采用恒河猴巨细胞病毒感染模型（RhCMV） 和SIVmac来研究离体粘膜树突状细胞（DC）和T细胞之间的相互作用。在目标2中，我们 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 无症状CMV复制显著促进HIV治疗后微生物易位的假说 疾病我们将确定用莱特莫韦抑制CMV复制对全身性生物标志物的影响。 微生物移位以及免疫激活和肠道屏障完整性直接在肠道粘膜中评估 组织中总之，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）， 确定基于改良疫苗安卡拉（MVA）的CMV疫苗是否可以增加全身和/或肠道- 归巢和粘膜CMV特异性T细胞反应在治疗HIV感染。治疗性抗CMV治疗失败 引起肠道归巢CMV特异性T细胞应答和减少粘膜CMV脱落的疫苗可 损害其在治疗的HIV感染中减少全身免疫激活的能力，并将突出需要 用于优化疫苗接种策略以改善粘膜反应。(Note：目标2和3不符合 NIH对临床试验的定义;这些目的中的辅助研究仅在既存研究的基础上增加额外措施 审判）。

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).