Inflammation and the vaginal metagenome in HIV acquisition

炎症和艾滋病毒感染中的阴道宏基因组

• 批准号: 8820884
• 负责人: Douglas Kwon
• 金额: $ 63.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-11 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820884
• 关键词: Address; Affect; Africa South of the Sahara; African; Anatomy; Area; Bacteria; Bacterial Vaginosis; Biological Markers; Cells; Cervical; Cervix Uteri; Chlamydia; Cohort Studies; Collaborations; Computational Biology; Contracts; Data; Data Set; Development; Environment; Estradiol; Female; Frequencies; Gene Expression; Genital system; Goals; Gonorrhea; HIV; HIV Infections; HIV risk; Health; Heterosexuals; High Risk Woman; High-Throughput Nucleotide Sequencing; Hormonal; Hormones; Human; Immune; Immune system; Immunologics; Immunology; Infant; Infection; Inflammation; Intervention; Life; Lymphocyte; Mediating; Medroxyprogesterone 17-Acetate; Metagenomics; Methods; Microbe; Mucous Membrane; Organism; Pathogenesis; Phenotype; Play; Population; Predisposition; Prevalence; Prevention strategy; Progesterone; Relative (related person); Reporting; Risk; Role; Sexually Transmitted Diseases; Simplexvirus; South Africa; Structure; Surveys; Technology; Transcript; Vagina; Variant; Viral; Virus; Woman; base; cohort; fungus; genital infection; hormonal contraception; immune activation; member; men; metagenome; microbial; microbial community; microbiome; nonhuman primate; peripheral blood; prevent; reproductive; reproductive hormone; research and development; response; sex; transmission process; vaginal microbicide

DESCRIPTION (provided by applicant): A critical area of research for the development of new interventions to halt HIV transmission is the characterization of the immunologic environment of the female reproductive tract (FRT). Globally, greater than 90% of HIV is transmitted following heterosexual intercourse and women are twice as likely to contract HIV from heterosexual sex than men. Mucosal tissues in the FRT therefore represent the frontline of transmission since they are the anatomic site at which HIV infection is first established in most new transmission cases. Despite this, HIV has largely been studied in the peripheral blood, which contains just 2% of lymphocytes and has been shown to have distinct immunologic features relative to those in the FRT. Based upon studies in nonhuman primates, soon after HIV exposure viral replication occurs within the mucosa of the cervix and vagina for 5-7 days prior to systemic dissemination. This early period in HIV transmission has been referred to as a "window of opportunity", since interventions which target HIV early in the FRT could prevent systemic viral dissemination. These observations suggest that the development of effective strategies to prevent HIV in women will require a detailed understanding of the critical FRT mucosal factors influencing HIV susceptibility. Recent results from the CAPRISA 004 vaginal microbicide trial suggest that elevated FRT inflammation increases risk of HIV acquisition by up to 14-fold. Microbially-driven sexually transmitted infections (STIs), bacterial vaginosis (BV), and reproductive hormones are known modulators of genital inflammation and increased HIV acquisition risk, suggesting the vaginal microbiome more broadly as well as reproductive hormones may play important roles in engendering FRT inflammation. The characterization of the vaginal microbiome to date has largely focused on the bacterial component, however other domains of life, including fungi, viruses, and potentially as-yet-incompletely-defined organisms, inhabit the FRT and may contribute to inflammation. New high throughput sequencing (HTS) technologies can comprehensively characterize the microbiome but have not been applied to the assessment of the vaginal microbiome beyond assessment of bacteria. The mechanism by which reproductive hormones, including endogenous progesterone and depot medroxyprogesterone acetate (the most common form of hormonal contraception used in sub-Saharan Africa), increase HIV acquisition remains incompletely understood. Collectively, these data indicate that both microbial and hormonal factors can significantly affect FRT inflammation and therefore potentially increase HIV acquisition in women. To fully define optimal strategies to prevent HIV transmission, a more complete understanding of the interdependent role of the vaginal microbiome, reproductive hormones, and genital inflammation is needed.

描述（由申请人提供）：开发新干预措施以阻止HIV传播的关键领域是女性生殖道（FRT）免疫学环境的表征。在全球范围内，异性恋性交后，超过90％的艾滋病毒是传播的，而女性从异性恋性别感染艾滋病毒的可能性是男性的两倍。因此，FRT中的粘膜组织代表了传播的前线，因为它们是在大多数新传播病例中首先建立HIV感染的解剖部位。尽管如此，HIV还是在外周血中进行了很大的研究，该血液仅包含2％的淋巴细胞，并且已被证明相对于FRT中的淋巴细胞具有不同的免疫学特征。基于在非人类灵长类动物中的研究，艾滋病毒暴露后不久，在全身传播前的子宫颈和阴道的粘膜内发生5-7天。艾滋病毒传播的早期时期被称为“机会之窗”，因为在FRT早期针对HIV的干预措施可以防止全身病毒传播。这些观察结果表明，制定预防妇女艾滋病毒的有效策略将需要详细了解影响HIV敏感性的关键FRT粘膜因素。 CAPRISA 004阴道杀菌剂试验的最新结果表明，FRT炎症升高可将HIV获取的风险提高多达14倍。微生物驱动的性传播感染（STI），细菌性阴道病（BV）和生殖激素是已知的生殖器炎症调节剂和增加的HIV获取风险，表明阴道微生物组更广泛地发挥了frt炎症，并且在生殖激素中起着重要的作用，并且可以发挥重要作用。 。迄今为止，阴道微生物组的表征主要集中在细菌成分上，但是生命的其他领域，包括真菌，病毒以及潜在的尚未完全定义的生物体，居住在FRT中，可能导致炎症。新的高通量测序（HTS）技术可以全面地表征微生物组，但尚未应用于对细菌评估的阴道微生物组的评估。生殖激素（包括内源性孕激素和墨西酯乙酸盐）（撒哈拉以南非洲使用的激素避孕的最常见形式）的生殖激素，增加的HIV收购仍然不完全理解。总的来说，这些数据表明，微生物和激素因子都会显着影响FRT炎症，因此可能增加女性的HIV获取。为了完全定义防止HIV传播的最佳策略，需要对阴道微生物组，生殖激素和生殖器炎症的相互依赖作用有更全面的了解。