权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结