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

描述（由申请人提供）：本提案的目的是研究避孕阴道环（CVR）对HIV感染和未感染女性阴道细菌的影响，以及HIV感染女性宫颈HIV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上，这些数据表明CVR对阴道细菌的有利影响，阴道细菌是对抗HIV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 阴道细菌的CVR，包括偶发性和持续性BV。目的是研究雌激素持续阴道给药是否能促进理想LB的健康阴道人群，从而降低发生和持续BV的风险。将入组BV女性患者，并每月进行评估，持续2个月，以收集关键乳酸杆菌和BV相关细菌（BVAB）的细菌特异性定量PCR（qPCR）检测。他们将在两个月后开始CVR，并在随后的4个月内每月返回进行评估。qPCR结果将用于确定存在或不存在CVR时阴道细菌浓度的变化。我们假设使用CVR将与通过临床状态、Nugent评分和BVAB qPCR评估的有利阴道变化相关。在目标2中，我们将测量使用CVR时可溶性粘膜宿主免疫应答和宫颈内免疫细胞群的关键参数，包括恢复BV背景下降低的保护性免疫介质，如SLPI、防御素、乳铁蛋白和内源性抗菌活性，以及宫颈内促炎细胞因子和活化T细胞数量的减少。在每次访视时收集宫颈拭子、细胞刷和宫颈阴道灌洗液，测定介质浓度和抗E。大肠杆菌、HIV和HSV-2。在目标3中，我们将在上述程序中招募的HIV感染但未接受抗逆转录病毒治疗（CD 4>350）的女性亚组中，评价CVR建立前后的HIV脱落。我们假设，CVR的使用将促进理想的乳酸杆菌占主导地位的非炎症阴道环境，降低生殖器HIV脱落的频率和数量，从而有助于降低HIV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.