Reproductive Hormones and their impact on HIV-1 acquisition

描述（由申请人提供）：女性生殖道是HIV-1感染的通道，具有多个解剖上不同的HIV-1潜在传播部位。在绝经前妇女中，月经周期内内源性生殖激素水平的波动会引起生殖道所有隔室的形态学、免疫学和蛋白质组学变化。超过3亿妇女通过激素避孕来调节生育。在进入更年期后，一些妇女开始外源性激素治疗，以减轻阴道萎缩的症状。内源性/外源性生殖激素对女性HIV-1感染的影响尚不清楚。该建议的统一假设是生殖激素通过影响调节HIV-1进入宫颈阴道道并在粘膜CD4+ T淋巴细胞和巨噬细胞中复制的宿主因子来改变HIV-1获得风险。我们提出以下具体目标。（目的1）量化外源性和内源性生殖激素对生殖道HIV-1易感性的影响；（目的2）确定生殖激素是否改变了HIV-1通过宫颈阴道上皮传播的机制；（目的3）量化生殖激素对女性生殖道HIV-1依赖因子的影响。我们将对健康的绝经前和绝经后未感染HIV-1的妇女进行纵向队列研究。受试者将在月经周期的不同阶段、开始激素避孕（高剂量口服避孕药vs低剂量口服避孕药vs DMPA）之前/之后以及开始雌激素乳膏之前/之后进行连续的宫颈和阴道活检。将组织置于器官培养中，对HIV-1感染的易感性将被量化，并与体内激素压力条件相关联。鉴于本《区域生殖健康报告》的压倒一切的重点是生殖健康是否成为艾滋病毒- 1的合并症，因此确定这一点至关重要

DESCRIPTION (provided by applicant): The female genital tract is a gateway to HIV-1 infection and presents multiple potential anatomically distinct sites for HIV-1 transmission. In pre-menopausal women, fluctuating levels of endogenous reproductive hormones during the menstrual cycle induce morphological, immunological and proteomic changes in all compartments of the genital tract. More than 300 million women regulate fertility by hormonal contraception. Upon reaching menopause, some women begin exogenous hormone treatment to alleviate symptoms of vaginal atrophy. The impact of endogenous/exogenous reproductive hormones on HIV-1 acquisition in women is unknown. The unifying hypothesis of this proposal is that reproductive hormones alter HIV-1 acquisition risk by impacting host factors that regulate HIV-1 entry into the cervicovaginal tract and replication in mucosal CD4+ T lymphocytes and macrophages. We propose the following specific aims. (Aim 1) To quantify the effect of exogenous and endogenous reproductive hormones on HIV-1 susceptibility of the reproductive tract, (Aim 2) To determine whether reproductive hormones alter the mechanisms responsible for HIV-1 transmission through cervicovaginal epithelia, (Aim 3) To quantify the effect of reproductive hormones on HIV-1 dependency factors in the female genital tract. We will assemble a longitudinal cohort of healthy pre- and post-menopausal HIV-1 uninfected women. Subjects will undergo serial cervical and vaginal biopsy during different phases of the menstrual cycle, before/after starting hormonal contraception (high dose oral contraceptives vs. low dose oral contraceptives vs. DMPA) and before/after starting estrogenic creams. Tissues will be placed in organ culture and susceptibility to HIV-1 infection will be quantified and correlated to n vivo conditions of hormonal pressure. Given that the overriding emphasis of this RFA is on whether reproductive health serves as a co-morbid condition for HIV- 1, it is critical to determine whether the hormonal environment that acts as a master regulator of the female reproductive tract truly impacts HIV-1 acquisition.