T-cell activation and exhaustion in the HIV-positive female genital tract

项目摘要 HIV感染是一种慢性病毒感染，如果不治疗，会导致CD4 T细胞区室的进行性丧失 最终导致艾滋病除了HIV易感性CD4 T细胞的丢失，慢性HIV感染的特征是 通过强大的全身免疫激活，包括B和T细胞激活和增殖以及升高的 促炎分子事实上，免疫激活水平与艾滋病密切相关 进展即使在抗逆转录病毒治疗（ART）开始和病毒抑制后， 与循环免疫功能失调有关，而不是恢复免疫静止。此外，免疫 在慢性感染的个体中，粘膜隔室如肠道中的激活可以持续存在，即使 艾滋病毒感染期间的这种慢性免疫激活最初主要是通过研究 尽管最近的研究表明，艾滋病毒相关的免疫激活可能表现为 不同的女人。鉴于妇女越来越多地受到艾滋病毒的影响，联合国艾滋病规划署报告说， 截至2020年，艾滋病毒感染者是妇女和女孩，很明显，我们对艾滋病的理解存在差距。 女性的免疫激活和功能障碍，特别是女性生殖道（FGT）粘膜。几 最初的研究表明，免疫激活在HIV感染女性的FGT中升高， 在治疗的最初一个月内不能将FGT免疫状态恢复到稳态水平。因此，我们建议 全面评估FGT在HIV感染情况下的免疫激活和功能障碍， 在没有病毒抑制的情况下长达24个月。在一组特征良好的感染和未感染艾滋病毒的女性队列中 在肯尼亚的蒙巴萨，我们将测试两个主要假设：1）我们假设艾滋病毒感染导致 在ART启动和病毒抑制后持续存在的FGT中增加的免疫激活，和2）我们 假设慢性和持续HIV感染导致粘膜组织内T细胞耗竭 FGT我们将通过包括对免疫激活的更彻底的调查来推进先前的研究 包括关注调节性T细胞（Treg）介导的免疫调节机制和T细胞耗竭 通过使用高通量单细胞分析，我们将研究长期病毒感染的影响。 抑制免疫激活和循环和FGT功能障碍。这将使我们能够更好 了解艾滋病毒感染如何可能导致不良FGT健康结果。

Project Summary HIV infection is a chronic viral infection that if untreated leads to progressive loss of the CD4 T cell compartment and eventually AIDS. In addition to loss of HIV-susceptible CD4 T cells, chronic HIV infection is characterized by robust systemic immune activation including B and T cell activation and proliferation and elevated levels of pro-inflammatory molecules. Indeed, the level of immune activation is strongly associated with HIV disease progression. Even upon antiretroviral therapy (ART) initiation and viral suppression, chronic HIV infection is associated with dysfunctional circulating immunity rather than a return to immune quiescence. Further, immune activation in mucosal compartments such as the gut can persist in chronically infected individuals, even with long-term ART. This chronic immune activation during HIV infection was first identified largely through study of men with HIV, though more recent studies have suggested that HIV-associated immune activation may manifest differently in women. Given that women are increasingly affected by HIV, with UNAIDS reporting that 53% of people living with HIV are women and girls as of 2020, it's evident that there is a gap in our understanding of immune activation and dysfunction in women, particularly within the female genital tract (FGT) mucosa. A few initial studies have suggested that immune activation is elevated in the FGT of women with HIV, and that ART does not restore FGT immune status to homeostatic levels within the initial month of treatment. Thus, we propose to comprehensively evaluate immune activation and dysfunction in the FGT in settings of HIV infection with or without viral suppression for up to 24 months. In a well-characterized cohort of women with and without HIV infection in Mombasa, Kenya, we will test two primary hypotheses: 1) We hypothesize that HIV infection leads to increased immune activation in the FGT that persists after ART initiation and viral suppression, and 2) We hypothesize that that chronic and persistent HIV infection leads to exhaustion of mucosal tissue T cells within the FGT. We will advance the prior research by including a more thorough investigation of immune activation including a focus on regulatory T cell (Treg)-mediated immunoregulatory mechanisms, and T cell exhaustion through use of high-throughput single-cell analysis, and we will examine the effects of longer-term viral suppression on immune activation and dysfunction in both the circulation and FGT. This will allow us to better understand how HIV infection may lead to negative FGT health outcomes.