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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要 HIV感染是一种慢性病毒感染，如果未经治疗导致CD4 T细胞室的逐渐丧失并最终艾滋病。除了丧失了HIV敏感的CD4 T细胞外，还表征了慢性HIV感染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水平促炎分子。实际上，免疫激活水平与HIV疾病密切相关进展。即使进行抗逆转录病毒疗法（ART）启动和病毒抑制，慢性HIV感染也是与功能失调的循环免疫力相关，而不是恢复免疫静止。此外，免疫诸如肠道等粘膜室中的激活也可以持续存在于长期感染的个体中，即使长期艺术。首先通过研究，首先确定了HIV感染期间这种慢性免疫激活艾滋病毒的男性尽管最近的研究表明，与艾滋病毒相关的免疫激活可能表现出来在女性方面有所不同。鉴于妇女越来越受艾滋病毒的影响，联合国艾滋病规划署报告说53％截至2020年，患有艾滋病毒的人是妇女和女孩，很明显，我们对女性的免疫激活和功能障碍，特别是在女性生殖道（FGT）粘膜内。几个最初的研究表明，HIV女性FGT的免疫激活升高，ART升高在治疗的最初月份内，不会将FGT免疫状态恢复到稳态水平。因此，我们建议在HIV感染的情况下，全面评估FGT中FGT中免疫激活和功能障碍的评估长达24个月没有病毒抑制。在有和没有艾滋病毒的妇女的符合人群中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感染铅为了增加在ART启动和病毒抑制后持续存在的FGT中的免疫激活，2）我们假设慢性和持续性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提高先前的研究包括关注调节T细胞（TREG）介导的免疫调节机制和T细胞耗尽通过使用高通量单细胞分析，我们将检查长期病毒的影响循环和FGT中免疫激活和功能障碍的抑制。这将使我们变得更好了解艾滋病毒感染如何导致FGT健康结果。