HIV Microbicides and the Vaginal Microbiome

HIV 杀菌剂和阴道微生物组

基本信息

批准号：
8143864
负责人：
Steven L. Zeichner
金额：
$ 43.84万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143864
关键词：
AIDS prevention Benign Biological Biological Assay Biological Sciences Cataloging Catalogs Cells Characteristics Clinical Clinical Trials Complementary DNA Complex Culture Techniques Data Development Doctor of Philosophy Environment Epidemic Equipment and supply inventories Exhibits Failure Funding Future Gastrointestinal tract structure Genes HIV HIV Infections HIV Seropositivity Health Human Hydrogen Peroxide Inflammation Inflammatory Lead Life Maintenance Measures Metabolic Methods Microbe Molecular Monitor Nonoxynol 9 Oligonucleotide Microarrays Oropharyngeal Patients Phase Phase III Clinical Trials Phylogenetic Analysis Placebos Population Population Decreases Prevalence Principal Investigator Production Protocols documentation Research Subjects Risk Sampling Sexual Transmission Specimen Swab Techniques Technology Time Toxic effect Ushercell Vagina Vaginal Douching Visit Woman bacteriocin base cellulose sulfate density design hydroxyethylcellulose meetings metagenome microbial microbial community microbicide microbiome pandemic disease phase 1 study phase 3 study pre-clinical prevent programs rRNA Genes response technology development transmission process vaginal microbicide

项目摘要

Vaginal HIV microbicides offer great promise to reduce HIV transmission, but phase 3 microbicide trials have failed. In some studies, patients using the microbicides had higher HIV transmission rates than did subjects using placebos. There is no clear explanation for these failures, but one hypothesis holds that microbicides alter the vaginal microbial flora in ways that increase inflammation or activate potential HIV host cells, enhancing transmission. Studies examining the effects of microbicides on the vaginal flora found few significant effects on the microbiome, but they used conventional culture techniques. Recent studies using molecular, culture-independent techniques showed that the flora in many human microbial environments, including the vagina, is much more complex than previously appreciated and that conventional culture techniques only detect a small fraction of the microbes in the environment. We propose to use these new culture-independent techniques to explore the hypothesis that microbicides alter the vaginal microbiome in ways that can potentially enhance HIV transmission via these specific aims: 1) Examine the vaginal microbial flora before and after microbicide application in a CONRAD repeat phase 1 study of nonoxynol-9 (N-9), cellulose sulfate (CS), and placebo using Affymetrix PhyloChip microarrays 2) Examine the portfolio of expressed genes in the vaginal microbiome before and after microbicide application using microbial cDNA sequencing in the phase 1 study, and 3) Examine the microbial species composition before and after microbicide application in the CONRAD CS phase 3 study that failed using the PhyloChip and direct 16S rRNA gene sequencing. The main milestone we propose to transition from the initial R21 phase of the project to the R33 phase is the demonstration that microbicide use leads to a significant alteration in the vaginal flora as assessed by the PhyloChip. Determining whether microbicide application is associated with vaginal microbiome changes that could enhance HIV transmission would aid understanding of the failure of the previous phase 3 trials and would help future microbicide development efforts because, if harmful changes in vaginal flora are associated with microbicide use, future microbicide development efforts would require careful measures to avoid inducing potentially harmful changes in the vaginal microbiome.

阴道 HIV 杀微生物剂为减少 HIV 传播提供了巨大希望，但第 3 阶段杀微生物剂试验失败了。在一些研究中，使用杀菌剂的患者与使用安慰剂的受试者相比，艾滋病毒传播率更高。没有明确的这些失败的解释，但一种假设认为杀菌剂改变了阴道微生物菌群会增加炎症或激活潜在的艾滋病毒宿主细胞，增强传输。研究杀菌剂对微生物的影响阴道菌群对微生物组几乎没有显着影响，但他们使用了传统的方法培养技术。最近的研究使用分子、非培养技术研究表明，包括阴道在内的许多人类微生物环境中的菌群比以前理解的要复杂得多，并且传统文化技术只能检测环境中的一小部分微生物。我们建议使用这些新的独立于文化的技术来探索以下假设：杀菌剂改变阴道微生物组，可能会增强艾滋病毒通过这些具体目标进行传播： 1) 在之前和之后检查阴道微生物菌群在 CONRAD 重复的 nonoxynol-9 (N-9) 第一阶段研究中应用杀菌剂后，硫酸纤维素 (CS) 和安慰剂，使用 Affymetrix PhyloChip 微阵列 2) 检查杀微生物剂前后阴道微生物组中表达基因的组合在第一阶段研究中使用微生物 cDNA 测序进行应用，以及 3) 检查 CONRAD 使用杀菌剂之前和之后的微生物物种组成使用 PhyloChip 和直接 16S rRNA 基因失败的 CS 3 期研究测序。我们建议从最初的 R21 阶段过渡的主要里程碑 R33 阶段的项目证明了杀菌剂的使用会导致根据 PhyloChip 评估，阴道菌群发生显着变化。确定杀菌剂的使用是否与阴道微生物群的变化有关可能会增强艾滋病毒的传播有助于理解以前的失败第三阶段试验将有助于未来的杀微生物剂开发工作，因为如果有害的话阴道菌群的变化与杀菌剂的使用、未来杀菌剂的使用有关发展努力需要采取谨慎的措施，以避免引发潜在的有害影响阴道微生物组的变化。