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: 9012013
• 负责人: Douglas Kwon
• 金额: $ 61.28万
• 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/9012013
• 关键词: Address; Affect; Africa South of the Sahara; 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; Reporting; Risk; Role; Sexually Transmitted Diseases; Simplexvirus; South Africa; South African; Structure; Surveys; Technology; Transcript; Vagina; Variant; Viral; Virus; Virus Replication; Woman; base; cohort; fungus; genital infection; genital microbiome; hormonal contraception; immune activation; member; men; metagenome; microbial; microbial community; microbiome; nonhuman primate; peripheral blood; prevent; reproductive hormone; reproductive tract; research and development; response; sex; transmission process; vaginal microbicide; vaginal microbiome

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 传播的一个关键研究领域是女性生殖道（FRT）免疫环境的表征。在全球范围内，超过 90% 的艾滋病毒是通过异性性行为传播的，女性通过异性性行为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，因为它们是大多数新传播病例中首先出现 HIV 感染的解剖部位。尽管如此，HIV 主要在外周血中进行研究，外周血仅含有 2% 的淋巴细胞，并且已被证明具有与 FRT 中不同的免疫学特征。根据对非人类灵长类动物的研究，HIV 暴露后不久，病毒就会在子宫颈和阴道粘膜内发生复制，持续 5-7 天，然后进行全身传播。 HIV 传播的早期阶段被称为“机会之窗”，因为在 FRT 早期针对 HIV 的干预措施可以防止系统性病毒传播。这些观察结果表明，制定预防女性艾滋病毒的有效策略需要详细了解影响艾滋病毒易感性的关键 FRT 粘膜因素。 CAPRISA 004 阴道杀菌剂试验的最新结果表明，FRT 炎症升高会使感染 HIV 的风险增加高达 14 倍。微生物驱动的性传播感染 (STIs)、细菌性阴道病 (BV) 和生殖激素是已知的生殖器炎症调节因子，并增加 HIV 感染风险，这表明更广泛的阴道微生物群以及生殖激素可能在引起 FRT 炎症中发挥重要作用。迄今为止，阴道微生物群的特征主要集中在细菌成分上，但其他生命领域，包括真菌、病毒和可能尚未完全确定的生物体，栖息在 FRT 中并可能导致炎症。新的高通量测序（HTS）技术可以全面表征微生物组，但尚未应用于除细菌评估之外的阴道微生物组评估。生殖激素，包括内源性黄体酮和长效醋酸甲羟孕酮（撒哈拉以南非洲最常见的激素避孕形式）增加艾滋病毒感染的机制尚不完全清楚。总的来说，这些数据表明微生物和激素因素都可以显着影响 FRT 炎症，因此可能增加女性感染艾滋病毒的机会。为了充分确定预防艾滋病毒传播的最佳策略，需要更全面地了解阴道微生物组、生殖激素和生殖器炎症之间相互依赖的作用。