Modulation of innate immunity,microbiome and HIV transmission by Depo-Provera

描述（由申请人提供）：流行病学研究表明，DMPA可能增加艾滋病毒感染和传播的风险。此外，Depo-Provera已被证明可以减弱疫苗保护恒河猴免受SIV感染的效力。使用激素避孕药具对艾滋病毒感染和传播的影响对计划生育政策具有深远影响，特别是在艾滋病毒传播率高的国家。虽然黄体酮明显增强了SIV/SHIV在恒河猴体内的阴道传播，但黄体酮类激素对女性HIV获取/传播的影响尚不清楚。我们假设注射DMPA改变免疫反应和宫颈阴道和结肠微生物组，这可能导致HIV感染和传播增加。本研究的目的是：(1)在纵向研究中确定Depo-Provera对全身和粘膜免疫系统以及对宫颈阴道和结肠微生物组的影响；(2)阐明mpa介导的体外、离体和宫颈移植模型中HIV感染/传播调节的免疫机制。在基线（卵泡期和黄体期）以及注射DMPA 4周和8周后采集血液、宫颈阴道标本和粪便样本。CD4+ T细胞的免疫学特征及其对HIV的易感性将被表征。我们将确定DMPA对宫颈阴道和结肠微生物组的时间影响。全球变化和特定分类群的变化将与免疫变化相关。我们的研究结果将更好地理解DMPA如何调节免疫反应和微生物组，从而为设计有效的HIV预防策略提供信息。

DESCRIPTION (provided by applicant): Epidemiologic studies demonstrate that DMPA may increase the risk of HIV acquisition and transmission. Additionally, Depo-Provera has been shown to attenuate the vaccine efficacy to protect rhesus macaques against SIV infection. The impact of hormonal contraceptive use on HIV acquisition and transmission has profound implications for polices on family planning, particularly in countries with high rates of HIV transmission. While progesterone clearly enhances vaginal transmission of SIV/SHIV in rhesus macaques, the effect of progestin-based hormone on HIV acquisition/transmission in women remains unresolved. We hypothesize that injectable DMPA alters immune responses and cervicovaginal and colonic microbiomes, which may lead to increased HIV acquisition and transmission. The aims of this proposal are designed to (1) determine the impact of Depo-Provera on the systemic and mucosal immune systems and on cervicovaginal and colonic microbiomes in a longitudinal study, and (2) to elucidate the immune mechanisms of MPA-mediated modulation of HIV infection/transmission in vitro, ex vivo and in cervical explant models. Blood, cervicovaginal specimens and stool samples will be collected at baseline (both follicular and luteal phases) and after 4, and 8 weeks of DMPA injection. The immunological profiles of CD4+ T cells and their susceptibility to HIV will be characterized. We will determine the temporal impact of DMPA on cervicovaginal and colonic microbiome. Global alteration and changes in specific taxa will be correlated with immunological changes. The results of our studies will provide a better understanding of how DMPA modulates immunologic responses and microbiomes, thereby informing the design of effective HIV prevention strategies.