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

HIV 阳性女性生殖道中 T 细胞的激活和耗竭

• 批准号: 10704271
• 负责人: Jennifer M Lund
• 金额: $ 81.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704271
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antigens; B-Lymphocytes; Bacterial Vaginosis; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Surface Proteins; Cells; Cervical; Cessation of life; Chronic; Circulation; Clinical; Cohort Analysis; Country; Data; Diagnosis; Disease; Disease Progression; Enrollment; Epidemic; Face; Female; Female genitalia; Flow Cytometry; Frequencies; Functional disorder; Genital; Genitalia; Goals; HIV; HIV Infections; HIV Seropositivity; HIV diagnosis; Health; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Immune; Immune System Diseases; Immunity; Immunologic Surveillance; Immunology; Impairment; Incidence; Individual; Infection; Inflammatory; Interruption; Intervention; Intestinal Mucosa; Investigation; Kenya; Lymphocytic choriomeningitis virus; Malignant neoplasm of cervix uteri; Measures; Mediating; Morbidity - disease rate; Mucous Membrane; Newly Diagnosed; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Predisposition; Prevalence; Prevention; Proliferating; Proxy; Regulatory T-Lymphocyte; Reporting; Research; Risk; Sampling; Severities; Sex Distribution; Simplexvirus; Site; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Viral; Virus Diseases; Virus Replication; Vulvovaginal Candidiasis; Woman; Women' s Health; Work; acquired immunity; antiretroviral therapy; cervical biopsy; chemokine; chronic infection; circulating biomarkers; cohort; cost; cytokine; effective therapy; exhaust; exhaustion; genital infection; girls; immune activation; immunological status; immunoregulation; improved; inflammatory marker; men; mortality; negative affect; novel strategies; pathogen; preventive intervention; programmed cell death protein 1; reproductive tract; sex; single cell analysis; standard of care; tumor; uptake; viral rebound

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.

项目概要 HIV 感染是一种慢性病毒感染，如果不治疗，会导致 CD4 T 细胞区室逐渐丧失 最终导致艾滋病。除了 HIV 易感 CD4 T 细胞的损失之外，慢性 HIV 感染的特征 通过强大的全身免疫激活，包括 B 细胞和 T 细胞的激活和增殖以及 促炎分子。事实上，免疫激活水平与艾滋病毒疾病密切相关 进展。即使在开始抗逆转录病毒治疗 (ART) 和病毒抑制后，慢性 HIV 感染仍会持续存在。 与循环免疫功能失调有关，而不是恢复免疫静止。此外，免疫 即使在慢性感染个体中，肠道等粘膜区室的激活也可能持续存在 长期艺术。 HIV 感染期间的这种慢性免疫激活主要是通过以下研究首次发现的： 男性艾滋病毒感染者，尽管最近的研究表明艾滋病毒相关的免疫激活可能会显现出来 女性则不同。鉴于女性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称，53% 的女性 截至 2020 年，艾滋病毒感染者是妇女和女孩，很明显，我们对艾滋病毒的理解存在差距 女性的免疫激活和功能障碍，特别是女性生殖道（FGT）粘膜内的免疫激活和功能障碍。几个 初步研究表明，感染 HIV 的女性 FGT 中的免疫激活水平升高，并且 ART 不会在治疗的最初一个月内将 FGT 免疫状态恢复至稳态水平。因此，我们建议 全面评估 HIV 感染或感染情况下 FGT 的免疫激活和功能障碍 长达 24 个月无病毒抑制。在一组特征明确的感染和未感染艾滋病毒的女性中 对于肯尼亚蒙巴萨的感染，我们将检验两个主要假设：1）我们假设 HIV 感染导致 FGT 中免疫激活的增加在 ART 启动和病毒抑制后持续存在，2) 我们 假设慢性和持续的 HIV 感染导致粘膜组织 T 细胞耗尽 FGT。我们将通过对免疫激活进行更彻底的研究来推进先前的研究 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，我们将检查长期病毒的影响 抑制循环和 FGT 中的免疫激活和功能障碍。这将使我们能够更好地 了解 HIV 感染如何导致负面 FGT 健康结果。