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

在全球范围内，年轻女性是感染艾滋病毒风险最大的弱势群体之一，突出了 需要安全、可接受和有效的预防产品。暴露前预防的结果(PrEP) 在这个高危年龄段，临床试验一直都令人失望，反映出行为和 生物学特征。PrEP的有效性反映了宿主对艾滋病毒的易感性和 暴露时宿主靶细胞中存在的药物浓度。最重要的生物学特征之一 调节HIV感染风险以及局部用药的药代动力学和疗效的因素 交付的PrEP产品是阴道微生物群。最近的研究强调了复杂的机制，通过 个别细菌及其代谢产物对几种不同PrEP的药代动力学产生不利影响 通过与人体细胞竞争药物摄取、抑制药物向人体细胞的转运或代谢而产生的药物 毒品。此外，在青春期和年轻女性中常见的细菌性阴道病与 艾滋病毒风险增加，可能反映了粘膜炎症。然而，将生态失调联系在一起的确切机制 对于炎症和微生物群对PrEP药代动力学的累积影响还没有定义。这 应用程序将解决这一关键的知识鸿沟，并测试阴道生物失调在 青春期和年轻成年女性通过促进粘膜炎症、增加艾滋病毒来降低PrEP的疗效 风险，以及降低当地药物的生物利用度。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16S rRNA测序(IgSeq)， 后基因组和后转录测序评估阴道生物失调和粘膜之间的联系 发炎。将从患有有症状细菌的青少年和年轻女性身上收集阴道拭子 标准护理治疗前后的阴道病(BV)和无症状对照(无BV) 与年龄、种族/民族和避孕用具的使用相匹配的频率。我们将对细菌总数进行鉴定 种群和IgA和/或包被和未包被的细菌，并将结果与生殖器测量相关联 阴道炎包括阴道活检组织中的基因表达。我们预测免疫球蛋白的组成 包被的细菌在BV治疗前后会有所不同，并与对照组相比，将鉴定出 导致生殖道发炎。使用临床样本，我们将确定细菌的累积影响 以替诺福韦为基础的PrEP(包括替诺福韦及其前体药物)的群落及其代谢物，评估哪些 机制主导，并探索潜在的干预措施，可能会促进更一致的药物 药理学。我们还将评估包括整合酶抑制剂在内的“下一代”PrEP产品。一起， 这些结果将为单独或联合应用药物的选择、剂量和配方提供理论依据 在年轻妇女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.