Hormone induced mucosal susceptibility and HIV risk in South African adolescents

 描述（由申请人提供）：在全球范围内，青春期女性是艾滋病毒性传播的最高风险，但也有意外怀孕的风险。撒哈拉以南非洲的青少年使用一系列避孕药具来防止怀孕。然而，激素避孕药与增加妇女感染艾滋病毒的风险有关。避孕药可以通过调节生殖器粘膜中HIV靶细胞的水平和/或易感性来影响HIV传播。避孕药可能通过影响阴道粘膜的细菌生态系统（微生物组）来机械地介导这些HIV靶细胞的变化。这项研究将首次评估避孕对南非青少年女性生殖道的两个方面的影响，这可能使她们感染艾滋病毒的风险增加：生殖器艾滋病毒靶细胞易感性和生殖器微生物组。目前有多种可用选项， 南非公共部门（SA）的有效、可逆避孕措施，本提案将评估其中三项措施。炔诺酮oenanthate（Net-En）是一种长效注射用炔雌醇，通常在撒哈拉以南非洲使用。其他避孕药含有雌激素和孕酮，包括需要每天服用的复方口服避孕药（COCP）和复方避孕阴道环（CCVR），每28天插入阴道。有一些证据表明，雌激素成分可能对艾滋病毒的获得提供保护作用。这项研究将评估一个假设，即在SA青少年女性中，与复方避孕药相比，仅孕激素避孕药导致阴道微生物组倾斜，导致阴道HIV靶细胞水平和易感性增加。为了解决我们的假设，我们将从一项单独的Net-En、COCP和CCVR随机对照试验中招募150名16至17岁的HIV阴性SA青少年。将在基线时采集样本并评价生殖道蛋白和基因表达、宫颈细胞刷样本中T细胞的表型/活化状态（通过流式细胞术）和生殖器微生物组（Aim 1）。然后将年轻女性随机分配到一种避孕方法，并纵向随访8个月。4个月后，所有参与者将随机更换避孕方法。目的2研究避孕药对生殖道蛋白和基因表达的影响，以及T细胞表型/活化状态。目标3将利用16 S和宏基因组深度测序评估避孕期间的阴道微生物组，并在宫颈外植体培养模型中评估这些目标的结果。这里概述的研究可能揭示为什么非洲青少年受艾滋病毒影响如此不成比例，并有可能极大地影响发展中国家青少年避孕的方式，以减少艾滋病毒感染，同时允许有效和安全的计划生育。

 DESCRIPTION (provided by applicant): Globally, adolescent females are at highest risk for sexual HIV transmission, but yet also at risk for unwanted pregnancies. Sub-Saharan African adolescents utilize a range of contraceptives to prevent pregnancy. However, hormonal contraceptives have been implicated in increasing HIV risk in women. Contraceptives could influence HIV transmission by mediating effects on the levels and/or susceptibility of HIV target cells in the genital mucosa. Contraceptives might mechanistically mediate these HIV target cell changes by impacting the bacterial ecosystem (microbiome) at the vaginal mucosa. This study will be the first to evaluate the effects of contraception on two aspects of South African adolescent female genital tract that may render them at increased risk of HIV: genital HIV target cell susceptibility, and the genital microbiome. There are currently multiple available options for effective, reversible contraception in the public sector of South Africa (SA), and three of these will be assessed in this proposal. Norethisterone oenanthate (Net-En) is a long-acting injectable progestin used commonly in sub Saharan Africa. The other contraceptives contain both estrogen and progestin, and include combination oral contraceptives (COCPs) which need to be taken daily, and the Combined Contraceptive Vaginal Ring (CCVR), which is inserted into the vagina every 28 days. There is some evidence that the estrogen component may provide a protective benefit for HIV acquisition. This study will evaluate the hypothesis that in SA adolescent women, progestin-only contraceptives result in a skewed vaginal microbiome that leads to an increase in vaginal HIV target cell levels and susceptibility, compared to combination contraceptives. To address our hypotheses we will enroll 150 HIV-negative SA adolescents between the ages of 16 and 17 years from a separate randomized controlled trial of Net-En, COCPs, and CCVRs. Samples will be collected and evaluated at baseline for genital tract protein and gene expression, the phenotype/activation state of T cells from cervical cytobrush samples (by flow cytometry), and the genital microbiome (Aim 1). The young women will then be randomized to a contraceptive method, and will be followed longitudinally for 8 months. After 4 months, all participants will have their contraceptive method randomly switched. Aim 2 will evaluate the effect of contraceptives on the genital tract protein and gene expression, as well as evaluate the phenotype/activation state of T cells. Aim 3 will evaluate the vaginal microbiome during contraceptive usage utilizing 16S and metagenomic deep sequencing, and evaluate the findings from these aims in a cervical explant culture model. The studies outlined here may uncover why African adolescents are so disproportionately affected by HIV and has the potential to dramatically impact how contraception is administered to adolescents in developing countries to reduce HIV acquisition while allowing effective and safe family planning.