How sex, host microenvironment, and immune responses shape acquisition of genital bacteria that increase HIV risk

项目总结 最近，几种与性传播没有经典联系的生殖器厌氧细菌 感染(非性传播感染)与艾滋病毒的异性传播增加有关，可能是通过诱导免疫 增强HIV目标细胞激活和向生殖器粘膜募集的反应。这个项目寻求 弥合有关获取和持续携带这一新的艾滋病毒风险因素的关键知识空白。我们的 长期目标是阐明生殖器微生物组组成的决定因素和生物学上的 将生殖器细菌与宿主对艾滋病毒的易感性联系起来的机制，并利用这一知识开发 预防艾滋病毒的创新解决方案。目的是了解异性传播的动力学。 了解与艾滋病毒风险有关的生殖器细菌，并确定影响艾滋病毒风险的非生物和生物因素 这些生殖器细菌在男性体内的获得和持久性。我们的中心假设是微扰 影响阴茎微生物群组成--包括生殖器细菌的获得、丧失或持续 与艾滋病毒风险相关--可预见的是一系列非生物和生物因素。这个项目的基本原理是 通过了解决定特定生物的获得、损失或持久性的非生物和生物因素 有了生殖器细菌，我们将能够确定和制定新的战略，以防止或减少殖民。 目的1.阐明生殖器细菌的性传播和阴茎的决定因素 性交后的微生物群。我们将通过以下方法来测试这一点：(I)表征青少年中存在的生殖器细菌菌株 男孩在首次性行为之前和之后(n=200)和(Ii)确定性交前宿主(阴茎)和 伴侣(阴道)生殖器的pH值、氧合作用、水分、代谢物、抗菌IgA和微生物群 获得或持续(性交后1、8和72小时)宿主生殖器细菌(n=106对夫妇)。 目的2.阐明抗菌治疗后阴茎微生物群的决定因素。我们将测试 这是通过比较治疗前和治疗后(第3、8和28天)1个对照组和4个对照组的阴茎微生物群来实现的 治疗臂，包括3种局部治疗：(I)2%克林霉素，(Ii)1%双氧水，(Iii)0.75%甲硝唑， 和(Iv)口服替硝唑。 目的3.验证非生物和生物因素对阴茎微生物群反应的影响 使用体外模型的微扰。我们将通过以下方式实现这一目标：(I)捐赠者阴道微生物组和 (Ii)在器官包皮模型中对阴茎微生物群局部使用抗菌剂，以评估非生物的效果 影响微生物组结果的因素和细菌菌株。 我们认为，拟议的研究是创新的，因为它代表了对现状的背离 通过阐明可传播的生物失调，并用绝对丰度指标来做到这一点，创新 研究设计，以及一种新颖的共同文化模式。这项拟议的研究具有重要意义，因为它 预计将揭示性行为和抗菌剂如何影响阴茎微生物群，以及是什么推动了结果。

PROJECT SUMMARY Recently, several genital anaerobic bacteria that are not classically associated with sexually transmitted infections (non-STI) were linked to increased heterosexual transmission of HIV, likely by inducing immune responses that enhances HIV target cell activation and recruitment to the genital mucosa. This project seeks to close critical knowledge gaps regarding acquisition and persistent carriage of this new HIV risk factor. Our long-term goals are to elucidate the determinants of genital microbiome composition and the biological mechanisms that link genital bacteria to host susceptibility to HIV, and to leverage this knowledge to develop innovative solutions to prevent HIV. The objective is to understand the heterosexual transmission dynamics of genital bacteria associated with HIV risk and to determine the abiotic and biotic factors that impact acquisition and persistence of these genital bacteria in men. Our central hypothesis is that perturbations affect penile microbiome composition—including acquisition, loss, or persistence of genital bacteria associated with HIV risk—predictably based a set of abiotic and biotic factors. The rationale for this project is that, by understanding the abiotic and biotic factors that determine acquisition, loss, or persistence of specific genital bacteria, we will be able to identify and develop new strategies to prevent or reduce colonization. Aim 1. Elucidate the sexual transmission of genital bacteria and the determinants of the penile microbiome after sex. We will test this by: (i) Characterize the genital bacteria strains present in adolescent boys before and after sexual debut (n = 200) and (ii) Determine the effect of pre-coital host (penile) and partner (vaginal) genital pH, oxygenation, moisture, metabolites, anti-bacteria IgA, and microbiome on the acquisition or persistence (1, 8, and 72 hour post-sex) of genital bacteria in the host (n = 106 couples). Aim 2. Elucidate the determinants of the penile microbiome after antimicrobial treatment. We will test this by comparing pre- and post- treatment (Day 3, 8, and 28) penile microbiomes in 1 control arm and 4 treatment arms, including 3 topical treatments: (i) 2% clindamycin, (ii) 1% H2O2, (iii) 0.75% metronidazole, and (iv) oral tinidazole. Aim 3. Validate the impact of abiotic and biotic factors on the penile microbiome response to perturbation using an in vitro model. We will achieve this aim by adding: (i) donor vaginal microbiome and (ii) topical antimicrobials to penile microbiome in organotypic foreskin model to assess the effect of abiotic factors and bacterial strains on microbiome outcome. The proposed research is innovative, in our opinion, because it represents a departure from the status quo by elucidating transmissible dysbiosis, and doing so with absolute abundance metrics, innovative study designs, and a novel co-culture model. The proposed research is significant because it is expected to reveal how sex and antimicrobials impact penile microbiome and what drives outcome.