Immunologic changes associated with three progestin-based contraceptives: characterizing immune profiles over one year and identifying factors that may alter HIV risk

项目摘要/摘要 这份提案概述了一项为期5年的转化性研究项目，以探索艾滋病毒的潜在机制 与外源性性激素(通过激素避孕药)的药理剂量相关的风险。 新出现的数据表明，某些荷尔蒙避孕药可能会诱导粘膜和系统免疫 可能会增加感染艾滋病毒风险的变化。虽然有几项研究的目的是描述 使用激素避孕药的妇女的免疫学变化及其性质和程度 由于研究设计的严密性的限制，免疫变化还没有得到充分的定义，而且 从统计学上讲，样本容量不足。关于这一影响的综合数据或比较数据有限 不同类型避孕药具对HIV易感性先天和获得性免疫标志物的影响。如果没有 在这项研究中，我们不能有效地为患者提供避孕选择方面的咨询。特征描述 潜在的个体因素，如细菌性阴道病(BV)的存在，可能会改变女性的 避孕药使用的风险概况，可能导致关于避孕选择和 将对全球健康产生深远影响，特别是在艾滋病毒流行地区。我们建议 前瞻性招募开始荷尔蒙避孕的未感染艾滋病毒的女性队列以确定 全身性和下生殖器轨迹先天和获得性免疫变化发生在1 年。这项研究将检验荷尔蒙避孕药会导致全身性和 粘膜免疫变化能够改变对包括艾滋病毒在内的疾病的易感性和/或反应 感染，这些影响在性质和程度上因避孕类型的不同而明显不同，并将 受阴道微环境的影响。其目的是：1)确定小鼠的免疫改变 与甲羟孕酮(DMPA)仓库相关的女性生殖器和系统免疫状况， 依托诺孕酮植入物(Eng-Implant)和左炔诺孕酮宫内节育器(LNG-IUD)。我们假设HIV的目标免疫 未感染艾滋病毒的高危女性在避孕后女性生殖道内的细胞将增加 入会仪式。此外，由于仅服用孕激素的避孕药预期的粘膜免疫变化是 在很大程度上，通过雌激素抑制，我们假设了LNG-IUD的影响(最小到 无抗雌激素作用)和Eng-Impot(具有较温和的抗雌激素作用)将明显不那么明显 与DMPA进行了比较。2)评价阴道微环境对生殖器功能的调节作用 暴露于这三种常见病毒后系统免疫状况的变化和组织感染性的变化 使用荷尔蒙避孕药。根据我们先前的发现，我们假设免疫学上的变化 激素避孕药的诱导作用在BV的发生中更为明显。这次会议的结果 拟议的研究可能对安全的个性化避孕措施具有重大的全球临床意义 为有艾滋病毒/艾滋病风险的妇女提供咨询和决策。

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year translational research project to explore the mechanisms underlying the HIV risk associated with pharmacologic doses of exogenous sex hormones (via hormonal contraceptives). Emerging data suggests that certain hormonal contraceptives may induce mucosal and systemic immune changes that could increase the risk of infection with HIV. While several studies have aimed to characterize immunologic changes in women using hormonal contraceptives, the nature and the magnitude of these immune changes have not been adequately defined due to limitations in study design rigor, and small and statistically underpowered sample sizes. There is limited comprehensive data or comparative data on the effect of different types of contraceptives on innate and adaptive immunologic markers of HIV susceptibility. Without this research, we cannot effectively counsel our patients on contraceptive selection. Characterization of potential individual-level factors, such as the presence of bacterial vaginosis (BV), that may alter a woman's risk profile with contraceptive use, could lead to individualized decision-making about contraceptive choice and would have profound implications for global health especially in HIV-endemic areas. We propose to prospectively recruit cohorts of HIV-uninfected women initiating hormonal contraception to characterize systemic and lower genital track innate and adaptive immunologic changes that occur over the course of 1 year. This study will test the overarching hypothesis that hormonal contraceptives induce systemic and mucosal immune changes capable of altering susceptibilities and/or responses to diseases including HIV infection, and that these effects vary markedly in nature and magnitude by contraceptive type and will be modified by the vaginal microenvironment. The aims are: 1) To determine the immunologic alterations in female genital and systemic immune profile associated with depot medroxyprogesterone acetate (DMPA), Etonogestrel impant (Eng-Implant) and Levonorgestrel IUD (Lng-IUD). We hypothesize that HIV target immune cells within the female genital tract of HIV-uninfected at-risk women will increase following contraceptive initiation. Further, because the anticipated mucosal immune changes with progestin-only contraceptives are, to a large extent, mediated via estrogen suppression, we hypothesize the impact of the Lng-IUD (with minimal to no anti-estrogen effect) and Eng-Implant (with milder anti-estrogen effect) will be significantly less pronounced compared with that of DMPA. 2) To evaluate the vaginal microenvironment as a moderator of genital and systemic immune profile changes and changes in tissue infectivity following exposure to these three commonly used hormonal contraceptives. Based on our earlier findings, we hypothesize that immunologic changes induced with hormonal contraception will be more pronounced in the setting of BV. The outcomes of the proposed study could have significant global clinical implications for safe individualized contraceptive counseling and decision-making for women at risk for HIV/AIDS.