Effects of contraceptive ring on vaginal microbiota, HIV shedding and local immun

描述(申请人提供)：这项建议的目的是研究避孕阴道环(CVR)对感染和不感染艾滋病毒的妇女阴道细菌的影响，以及对艾滋病毒感染妇女宫颈艾滋病毒脱落的影响，并将这些变化与可溶性粘膜宿主免疫防御的关键措施联系起来。我们将建立在有限的数据基础上，这些数据表明CVR对阴道细菌有良好的效果，这构成了预防艾滋病毒感染和其他性传播感染(STI)的关键第一道防线。在目标1中，我们将确定 对阴道细菌的CVR，包括偶发性和持久性BV。其目的是研究持续的雌激素阴道给药是否能促进健康的阴道人群获得理想的LB值，从而降低发生BV和持续BV的风险。患有BV的妇女将接受为期两个月的每月登记和评估，以收集关键乳杆菌和BV相关细菌(BVAB)的细菌特异性定量聚合酶链式反应(QPCR)分析。他们将在两个月后启动CVR，并将在随后的4个月内每月返回进行评估。定量聚合酶链式反应结果将被用来确定在没有CVR存在的情况下阴道细菌浓度如何变化。我们假设CVR的使用将与通过临床状态、Nugent评分和BVAB qPCR评估的良好的阴道改变相关。在目标2中，我们将测量CVR使用时可溶性粘膜宿主免疫反应和宫颈免疫细胞群的关键参数，包括恢复在BV环境中减少的保护性免疫介质，如SLPI、防御素、乳铁蛋白和内源性抗菌活性，以及减少促炎细胞因子和激活的T细胞数量。每次就诊时将收集宫颈拭子、细胞刷子和宫颈阴道冲洗液，并测量介质浓度和对大肠杆菌、艾滋病毒和HSV-2的抗菌活性。在目标3中，我们将评估在CVR建立之前和之后，在上述程序中登记的未接受抗逆转录病毒治疗的艾滋病毒感染者中的一部分妇女的艾滋病毒脱落率(CD4&GT；350)。我们假设，CVR的使用将促进理想的以乳杆菌为主的非炎性阴道环境，减少生殖器艾滋病毒脱落的频率和数量，从而有助于降低艾滋病毒传播风险。

DESCRIPTION (provided by applicant): The objective of this proposal is to study effects of a contraceptive vaginal ring (CVR) on vaginal bacteria in women with and without HIV, and cervical HIV shedding in HIV-infected women, and relates these changes to key measures of soluble mucosal host immune defense. We will build on limited data suggesting a favorable effect of CVR on vaginal bacteria, which comprise a critical first line of defense against infectio with HIV and other sexually transmitted infections (STI). In Aim 1, we will determine the effect of the CVR on vaginal bacteria, including incident and persistent BV. The goal is to study whether sustained vaginal delivery of estrogen promotes healthy vaginal populations of desirable LB, and thus reduces risk of incident and persistent BV. Women with BV will be enrolled and assessed monthly for two months to collect bacterium-specific quantitative PCR (qPCR) assays for key lactobacilli and BV- associated bacteria (BVAB). They will initiate CVR after two months and will return monthly over 4 subsequent months for assessment. qPCR results will be used to determine how concentrations of vaginal bacteria change in presence of absence of CVR. We hypothesize that CVR use will be associated with favorable vaginal change assessed by clinical status, Nugent score, and BVAB qPCR. In Aim 2, we will measure key parameters of the soluble mucosal host immune response and endocervical immune cell populations with CVR use, including restoration of protective immune mediators that are decreased in the setting of BV such as SLPI, defensins, lactoferrrin, and endogenous antimicrobial activity, and reduction in pro-inflammatory cytokines and the number of activated T-cells in the endocervix. Endocervical swabs, cytobrushes and cervicovaginal lavage will be collected at each visit and concentrations of mediators and antimicrobial activity against E. coli, HIV and HSV-2 measured. In Aim 3, we will evaluate HIV shedding prior to and after establishment of the CVR in a subset of women enrolled in the above procedures who are HIV-infected and not on antiretroviral therapy (CD4>350). We hypothesize that CVR use will promote a desirable Lactobacillus- predominant, non-inflammatory vaginal environment with reduced frequency and quantity of genital HIV shedding, thereby contributing to a reduction of HIV transmission risk.