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可能会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效力，以保护恒河猴免受SIV感染。荷尔蒙避孕药的使用对艾滋病毒感染和传播的影响对计划生育政策有着深远的影响，特别是在艾滋病毒传播率高的国家。虽然孕酮明显增强了SIV/SIV在恒河猴中的阴道传播，但基于孕激素的激素对女性艾滋病毒感染/传播的影响仍未解决。我们推测，可注射的DMPA改变了免疫反应以及宫颈、阴道和结肠的微生物群，这可能导致艾滋病毒感染和传播的增加。这项建议的目的是(1)在纵向研究中确定Depo-Provera对系统和粘膜免疫系统以及对宫颈、阴道和结肠微生物群的影响，以及(2)在体外、体外和宫颈移植模型中阐明MPA介导的调节HIV感染/传播的免疫机制。将在基线(卵泡期和黄体期)以及注射DMPA后4周和8周收集血液、宫颈阴道样本和粪便样本。将描述CD4T细胞的免疫学特征及其对HIV的敏感性。我们将确定DMPA对宫颈、阴道和结肠微生物群的时间影响。全球变化和特定类群的变化将与免疫学变化相关。我们的研究结果将使我们更好地了解DMPA如何调节免疫反应和微生物群，从而为设计有效的艾滋病毒预防策略提供信息。

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.