Hormone induced mucosal susceptibility and HIV risk in South African adolescents

 描述(申请人提供)：在全球范围内，青春期女性感染艾滋病毒的风险最高，但也面临意外怀孕的风险。撒哈拉以南非洲的青少年使用一系列避孕药具来避孕。然而，荷尔蒙避孕药被认为与增加女性感染艾滋病毒的风险有关。避孕药具可通过调节生殖器粘膜中艾滋病毒目标细胞的水平和/或易感性来影响艾滋病毒的传播。避孕药可能通过影响阴道粘膜的细菌生态系统(微生物群)来机械地调节这些HIV靶细胞的变化。这项研究将首次评估避孕对南非青春期女性生殖道的两个方面的影响，这两个方面可能会增加她们感染艾滋病毒的风险：生殖器艾滋病毒靶细胞易感性和生殖器微生物群。目前有多个可用选项可用于 南非公共部门的有效、可逆避孕措施，其中三项将在本提案中进行评估。烯雌酚(NET-EN)是一种长效可注射孕激素，通常在撒哈拉以南非洲使用。其他避孕药同时含有雌激素和孕激素，包括每天需要服用的联合口服避孕药(COCP)，以及每28天插入阴道的联合避孕环(CCVR)。有一些证据表明，雌激素成分可能会对艾滋病毒的感染起到保护作用。这项研究将评估这样一种假设，即在SA青春期女性中，与联合避孕药相比，仅使用孕激素的避孕药会导致阴道微生物群扭曲，从而导致阴道艾滋病毒目标细胞水平和敏感性的增加。为了解决我们的假设，我们将从一项单独的随机对照试验中招募150名艾滋病毒阴性的SA青少年，年龄在16岁到17岁之间，这些试验包括NET-EN、COCP和CCVR。将收集样本并在基线上评估生殖道蛋白和基因表达、宫颈细胞刷样中T细胞的表型/激活状态(通过流式细胞仪)以及生殖器微生物组(目标1)。然后，这些年轻女性将被随机分配到一种避孕方法，并将被纵向跟踪8个月。4个月后，所有参与者将随机切换他们的避孕方法。目的2评价避孕药对生殖道蛋白质和基因表达的影响，以及T细胞的表型/活化状态。目的3将利用16S和元基因组深度测序来评估避孕用药过程中的阴道微生物组，并在宫颈组织培养模型中评估这些目标的结果。这里概述的研究可能会揭示为什么非洲青少年感染艾滋病毒的比例如此之高，并有可能极大地影响发展中国家青少年如何采取避孕措施，以减少艾滋病毒的感染，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.