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

阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响

• 批准号: 10372984
• 负责人: Betsy C. Herold
• 金额: $ 53.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372984
• 关键词: 15 year old; 16S ribosomal RNA sequencing; AIDS prevention; Active Biological Transport; Address; Adenine; Adherence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Anti-Retroviral Agents; Bacteria; Bacterial Vaginosis; Behavioral; Binding; Biologic Characteristic; Biological Assay; Biological Availability; Biological Factors; Biopsy; Black race; Cell Separation; Cells; Centers for Disease Control and Prevention (U.S.); Cervical; Clinical; Clinical Research; Clinical Trials; Complex; Contraceptive Usage; Dapivirine; Data; Development; Diffuse; Dose; Drug Formulations; Drug Kinetics; Drug Transport; Effectiveness; Endocytosis; Epidemic; Equilibrium; Ethnic Origin; Female; Flow Cytometry; Formulation; Frequencies; Gardnerella; Gel; Gene Expression; HIV; HIV risk; Heterosexuals; Human; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; In Vitro; Incubated; Individual; Infection; Inflammation; Inflammatory; Integrase; Integrase Inhibitors; Intervention; Knowledge; Lactobacillus; Latino; Link; Liquid substance; Measures; Metabolic; Metagenomics; Metronidazole; Mucositis; Mucous Membrane; Organic Anion Transporters; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Population; Predisposition; Prevention; Prodrugs; Property; Public Health; Race; Risk; Sampling; Seminal fluid; Swab; T-Lymphocyte; Techniques; Technology; Tenofovir; Testing; Time; Tissues; Topical application; Translating; United States; Vagina; Vulnerable Populations; Woman; age group; bacterial community; base; cervicovaginal; cohort; design; drug metabolism; dysbiosis; epidemiology study; fecal microbiome; high risk; men; metabolome; metatranscriptomics; microbial community; microbiome; microbiota; next generation; novel; oral care; phase 1 study; phase III trial; pre-exposure prophylaxis; preclinical development; reproductive tract; response; standard of care; uptake; vaginal microbiome; vaginal microbiota; young woman

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.

在全球范围内，年轻妇女代表了有艾滋病毒收购风险的最脆弱的群体之一 需要安全，可接受和有效的预防产品。暴露前预防的结果（PREP） 在这个高风险的年龄组中，临床试验令人失望，反映了行为和 生物学特征。准备的效率反映了宿主对艾滋病毒易感性和 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 调节艾滋病毒获取风险和药代动力学和效率的因素 传递的准备产品是阴道微生物组。最近的研究强调了复杂机制 单个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 通过与人类细胞竞争药物吸收药物，抑制药物转运到人细胞或代谢 毒品。此外，在青春期和年轻女性中常见的细菌阴道与 艾滋病毒风险增加，可能反映粘膜注射。但是，连接营养不良的精确机制 尚未定义炎症和微生物组对药代动力学的累积作用。这 应用将解决此关键知识差距，并检验阴道失调的总体假设 青少年和年轻的成年女性通过促进粘膜炎症来降低准备效率，增加HIV 风险，降低当地药物的生物利用度。我们将使用包括流式细胞仪在内的尖端技术 免疫球蛋白涂层细菌的基于细菌细胞分选结合16S rRNA测序（IGSEQ）， 宏基因组和元转录组测序评估阴道营养不良与粘膜之间的联系 炎。阴道拭子将从有症状细菌的青少年和年轻女性中收集 护理标准治疗前后的阴道化（BV）和来自非对称对照（无BV）的阴道化（BV） 年龄，种族/种族和避孕药的使用频率。我们将表征总细菌 种群以及IgA和/或IgG涂有和未涂层的细菌，并将发现与生殖器的测量结果相关 道炎症，包括阴道活检组织中的基因表达。我们预测Ig的组成 涂层细菌在BV治疗前后将有所不同，并与对照组进行比较，并将确定细菌 驱动生殖道感染。使用临床样品，我们将确定细菌的累积作用 社区及其在基于Tenofovir的Prep（包括Tenofovir及其前药）上的代谢组 机制主导并探索潜在的干预措施，这些干预措施可能会促进更一致的药物 药理。我们还将评估包括集成酶抑制剂在内的“下一代”准备产品。一起， 这些结果将为选择，给药和配制药物的选择提供理由 最佳预防年轻女性的艾滋病毒。