Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)

在全球范围内，青年妇女是最易感染艾滋病毒的群体之一，这突出表明， 需要安全、可接受和有效的预防产品。暴露前预防（PrEP）的结局 在这个高危年龄组的临床试验一致令人失望，反映了行为和 生物学特性PrEP的有效性反映了宿主对HIV的易感性和 暴露时宿主靶细胞中存在的药物浓度。最重要的生物学之一 调节HIV感染风险以及局部给药的药代动力学和疗效的因素 递送的PrEP产品是阴道微生物组。最近的研究强调了复杂的机制， 个别细菌及其代谢产物对几种不同的PrEP的药代动力学产生不利影响 药物通过与人体细胞竞争药物摄取，抑制药物转运到人体细胞中，或代谢 毒品此外，细菌性阴道病，这是常见的青少年和年轻妇女， HIV风险增加，可能反映粘膜炎症。然而，生态失调的确切机制 炎症和微生物组对PrEP药代动力学的累积效应尚未确定。这 应用程序将解决这一关键的知识差距，并测试总体假设，阴道生态失调， 青少年和年轻成年女性通过促进粘膜炎症，增加艾滋病毒感染， 风险和降低局部药物生物利用度。我们将使用包括流式细胞术在内的尖端技术 基于免疫球蛋白包被细菌的细菌细胞分选结合16 S rRNA测序（IgSeq）， 宏基因组和元转录组测序评估阴道微生态失调和粘膜病变之间的联系 炎症将从有症状的细菌感染的青少年和年轻女性中采集阴道拭子。 标准护理治疗前后的阴道病（BV）和无症状对照（无BV）， 与年龄、人种/种族和避孕药具使用情况相匹配的频率。我们将描述细菌总数 人群和伊加和/或IgG包被和未包被的细菌，并将结果与生殖器 包括阴道活检组织中基因表达在内的阴道炎症。我们预测IG的组成 与对照相比，BV处理前后包被的细菌将不同， 导致生殖道炎症使用临床样本，我们将确定细菌的累积效应， 社区及其代谢组对替诺福韦为基础的PrEP（包括替诺福韦及其前体药物），评估 机制占主导地位，并探索可能促进更一致的药物治疗的潜在干预措施。 药理学我们还将评估“下一代”PrEP产品，包括整合酶抑制剂。在一起， 这些结果将为单独或联合使用药物的选择、剂量和制剂提供理论依据， 在年轻女性中最佳预防艾滋病毒。

Globally, young women represent one of the most vulnerable groups at risk for HIV acquisition highlighting the need for safe, acceptable and effective prevention products. Outcomes in pre-exposure prophylaxis (PrEP) clinical trials have been uniformly disappointing in this high-risk age group, reflecting both behavioral and biological characteristics. The efficacy of PrEP reflects a balance between host susceptibility to HIV and the concentration of drug present in host target cells at the time of exposure. One of the most important biological factors that modulates both the risk of HIV acquisition and the pharmacokinetics and efficacy of topically delivered PrEP products is the vaginal microbiome. Recent studies highlight the complex mechanisms by which individual bacteria and their metabolic products adversely affect the pharmacokinetics of several different PrEP drugs by competing with human cells for drug uptake, inhibiting drug transport into human cells, or metabolizing drugs. Moreover, bacterial vaginosis, which is common in adolescent and young women, is associated with increased HIV risk, possibly reflecting mucosal inflammation. However, the precise mechanisms linking dysbiosis with inflammation and the cumulative effect of the microbiome on PrEP pharmacokinetics are not defined. This application will address this critical knowledge gap and test the overarching hypothesis that vaginal dysbiosis in adolescent and young adult women reduces PrEP efficacy by promoting mucosal inflammation, increasing HIV risk, and decreasing local drug bioavailability. We will use cutting edge technologies including flow cytometry based bacterial cell sorting of immunoglobulin-coated bacteria combined with 16S rRNA sequencing (IgSeq), metagenomic and metatranscriptomic sequencing to evaluate the link between vaginal dysbiosis and mucosal inflammation. Vaginal swabs will be collected from adolescent and young women with symptomatic bacterial vaginosis (BV) before and after standard of care treatment and from asymptomatic controls (no BV) who are frequency matched for age, race/ethnicity and contraceptive use. We will characterize the total bacterial population and the IgA and/or IgG coated and uncoated bacteria and correlate findings with measures of genital tract inflammation including gene expression in vaginal biopsy tissue. We predict that the composition of Ig coated bacteria will differ before and after BV treatment and compared to controls and will identify bacteria that drive genital tract inflammation. Using the clinical samples, we will determine the cumulative effects of bacterial communities and their metabolome on tenofovir-based PrEP (including tenofovir and its prodrugs), assess which mechanisms dominate, and explore potential interventions that might promote more consistent drug pharmacology. We will also evaluate “next-generation” PrEP products including integrase inhibitors. Together, these results will provide rationale for the selection, dosing and formulation of drugs alone or in combination for optimal prevention of HIV in young women.