MicroRNA Predictors of HIV Risk in Reproductive Age Women

育龄妇女 HIV 风险的 MicroRNA 预测因子

• 批准号: 10376860
• 负责人: RAINA N. FICHOROVA
• 金额: $ 80.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-13 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376860
• 关键词: AIDS prevention; Africa South of the Sahara; Age; Anatomy; Bacterial Vaginosis; Biological; Blood Circulation; Breast Feeding; Cervical; Clinical; Communication; Communities; Complex; Conduct Clinical Trials; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Development; Diagnostic; Disease; Distant; Etiology; Face; Female genitalia; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV risk; HIV-1; Health; Hormonal; Hormones; Immune; Immunity; Incidence; Knowledge; Laboratories; Luteal Phase; Mediating; MicroRNAs; Mission; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Natural Immunity; Oral Contraceptives; Outcome; Pathway interactions; Population Heterogeneity; Predisposing Factor; Predisposition; Pregnancy; Prevention; Preventive; Progestins; Prospective cohort; Proteins; Proteomics; Public Health; RANTES; RNA; Recurrence; Regulation; Research; Risk; Risk Factors; Role; SLPI gene; Sampling; Serum; Signal Transduction; Statistical Models; Technology; Testing; Therapeutic; Time; Translations; Uganda; United States; United States National Institutes of Health; Untranslated RNA; Unwanted pregnancy; Ursidae Family; Vagina; Validation; Visit; Vulnerable Populations; Woman; Work; Zimbabwe; bioinformatics tool; cervicovaginal; circulating microRNA; cohort; design; differential expression; disability; dysbiosis; epigenetic regulation; extracellular vesicles; functional genomics; fundamental research; hormonal contraception; human female; improved; infection burden; insight; metagenome; microbiome; microbiota; new technology; novel; novel diagnostics; novel therapeutics; peripheral blood; predictive modeling; racial diversity; rational design; reproductive; response; transcriptomics; transmission process; vaginal microbiota

Current contraceptive options for women facing risk of HIV are limited. Despite evidence of increased risk of HIV acquisition associated with progestin-only contraceptives, predominantly DMPA, millions of women around the world continue using DMPA with an estimated >140 million using this or other hormonal contraceptives (HC). Moreover, DMPA is the most common contraceptive method in sub-Saharan Africa – the region that bears an estimated 70% of the global HIV-infection burden. Vaginal dysbiosis, another risk factor for HIV acquisition, is also more common in women in this high HIV incidence region. Insights from our research gained in one of the largest prospective cohorts designed to investigate the association between HC use and HIV acquisition (HC- HIV study), support the following paradigms: 1) DMPA users develop aberrant cervical and systemic immunity that precedes HIV seroconversion and 2) altered vaginal microbiota potentiates DMPA effects on cervical immunity. The lack of understanding of the molecular mechanisms underlying the HC-immunity-microbiota interactions leading to increased HIV susceptibility is limiting efforts to design safer contraceptive and preventive technologies. We propose a novel hypothesis-driven paradigm to test the role of micro-RNAs (miRNAs) in risk of HIV acquisition. Because of their stability in the circulation, ubiquitous gene silencing function, and emerging evidence of important roles of small non-coding RNAs in controlling HIV infection, miRNAs are attractive novel therapeutic and diagnostic targets. No information on miRNA expression in association with HC and abnormal vaginal microbiota is currently available. To fill this gap in mechanistic understanding, we propose the following aims: (1) Identify circulating aberrant miRNAs associated with risk of HIV-1 acquisition and innate immunity in reproductive age women; (2) Identify hormonally regulated miRNAs predictive of HIV risk and immune imbalance that precedes HIV seroconversion; (3) Identify miRNAs regulated by vaginal dysbiosis that may facilitate communication between systemic and mucosal immunity imbalance associated with HIV risk. We will utilize ~1000 banked sera and cervicovaginal secretions from the longitudinal HC-HIV cohorts in Uganda and Zimbabwe and four clinical trials conducted in the United States representing a racially diverse population. Comprehensive demographic, clinical and laboratory information available on known major factors for HIV risk in these cohorts will allow robust statistical modeling. We will use rigorous state-of-the-art technologies and bioinformatics tools for transcriptomic, proteomic and functional genomics to generate profiles of differentially expressed miRNAs and targeted genes and pathways with roles in the risk of HIV acquisition. This research provides a unique opportunity to elucidate and validate the complex associations between endogenous and exogenous hormones, bacterial vaginosis and HIV-1 through analysis of miRNAs underlying shared biological mechanisms.

目前面临艾滋病毒感染风险的妇女的避孕选择有限。尽管有证据表明艾滋病毒的风险增加