Hormone induced mucosal susceptibility and HIV risk in South African adolescents

南非青少年激素诱导的粘膜敏感性和艾滋病毒风险

• 批准号: 9045671
• 负责人: Heather Beryl Jaspan
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045671
• 关键词: 17 year old; AIDS prevention; Address; Adherence; Adolescent; Affect; Africa South of the Sahara; African; Age; Antiviral Agents; Bacterial Vaginosis; Cells; Cervical; Clinic; Clinical Trials; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Developing Countries; Ecosystem; Eligibility Determination; Enrollment; Estrogens; Evaluation; Family Planning; Female Adolescents; Flow Cytometry; Formulation; Funding; Gene Expression; Genetic Crossing Over; Genital system; Goals; HIV; HIV Infections; HIV risk; HIV-1; Health; Hormones; Immune; Immune Cell Activation; Immunology; Inflammation; Inflammation Mediators; Injectable; Licensing; Measures; Mediating; Medroxyprogesterone 17-Acetate; Metagenomics; Modeling; Mucositis; Mucous Membrane; Norethindrone; Oral Contraceptives; Participant; Phenotype; Policies; Population; Predisposition; Pregnancy; Progestins; Public Sector; Randomized; Randomized Controlled Trials; Research; Research Infrastructure; Risk; Sampling; South Africa; South African; T-Cell Activation; T-Lymphocyte; Unwanted pregnancy; Vagina; Vaginal Ring; Woman; Youth; aged; chemokine; cohort; cytokine; deep sequencing; design; genital microbiome; high risk; hormonal contraception; microbial; microbiome; microbiota; microorganism; pill; prevent; programs; protein expression; randomized trial; reproductive tract; response; sexual HIV transmission; sexually active adolescent; transcriptome sequencing; transmission process; vaginal microbiome; young woman

 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.

 描述（由申请人提供）：在全球范围内，青春期女性艾滋病毒性传播的风险最高，但也面临意外怀孕的风险。撒哈拉以南非洲青少年使用一系列避孕药具来预防怀孕。然而，激素避孕药会增加女性感染艾滋病毒的风险。避孕药可以通过调节生殖器粘膜中艾滋病毒靶细胞的水平和/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两个方面的影响，这两个方面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（SA）公共部门的有效、可逆避孕措施，本提案将评估其中三个。庚酸炔诺酮 (Net-En) 是一种长效注射孕激素，常用于撒哈拉以南非洲地区。其他避孕药同时含有雌激素和孕激素，包括需要每天服用的复方口服避孕药 (COCP) 和每 28 天插入阴道的复方避孕阴道环 (CCVR)。有一些证据表明雌激素成分可能为艾滋病毒感染提供保护作用。这项研究将评估以下假设：在南澳青春期女性中，与复方避孕药相比，纯孕激素避孕药会导致阴道微生物群失调，从而导致阴道 HIV 靶细胞水平和易感性增加。为了验证我们的假设，我们将从 Net-En、COCP 和 CCVR 的单独随机对照试验中招募 150 名年龄在 16 至 17 岁之间的 HIV 阴性 SA 青少年。将收集样本并在基线时评估生殖道蛋白和基因表达、宫颈细胞刷样本中 T 细胞的表型/激活状态（通过流式细胞术）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采用避孕方法，并进行为期 8 个月的纵向随访。 4个月后，所有参与者将随机更换避孕方法。目标 2 将评估避孕药对生殖道蛋白质和基因表达的影响，以及评估 T 细胞的表型/激活状态。目标 3 将利用 16S 和宏基因组深度测序评估避孕药具使用过程中的阴道微生物组，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会揭示为什么非洲青少年如此严重地受到艾滋病毒的影响，并有可能极大地影响发展中国家青少年的避孕方式，以减少艾滋病毒的感染，同时允许有效和安全的计划生育。