Inflammation and the vaginal metagenome in HIV acquisition

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，90%以上的艾滋病毒是通过异性性交传播的，妇女通过异性性交感染艾滋病毒的可能性是男子的两倍。因此，FRT中的粘液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次建立HIV感染的解剖部位。尽管如此，HIV主要是在外周血中研究的，外周血中仅含有2%的淋巴细胞，并且已被证明相对于FRT中的淋巴细胞具有独特的免疫学特征。基于对非人灵长类动物的研究，HIV暴露后不久，病毒复制在子宫颈和阴道粘膜内发生，持续5-7天，然后全身传播。这一艾滋病毒传播的早期阶段被称为“机会之窗”，因为在首次登记治疗的早期阶段针对艾滋病毒的干预措施可以防止病毒的全身传播。这些观察结果表明，制定有效的策略，以防止艾滋病毒在妇女将需要一个详细的了解的关键FRT粘膜因素影响艾滋病毒的易感性。CAPRISA 004阴道杀微生物剂试验的最新结果表明，FRT炎症升高会使HIV感染风险增加14倍。微生物驱动的性传播感染（STI），细菌性阴道病（BV）和生殖激素是生殖器炎症和增加HIV获得风险的已知调节剂，这表明更广泛的阴道微生物组以及生殖激素可能在产生FRT炎症中发挥重要作用。迄今为止，阴道微生物组的表征主要集中在细菌组分上，然而其他生命领域，包括真菌，病毒和潜在的尚未完全定义的生物体，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，但尚未应用于评估细菌以外的阴道微生物组。生殖激素，包括内源性孕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仍不完全清楚。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，因此可能会增加女性的HIV感染。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的相互依赖作用。

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.