HIV Microbicides and the Vaginal Microbiome

阴道HIV杀微生物剂为减少HIV传播提供了巨大的希望，但第3阶段 杀微生物剂试验失败了。在一些研究中，使用杀微生物剂的患者 艾滋病毒传播率高于使用安慰剂的受试者。没有明确 这些失败的解释，但一种假设认为，杀微生物剂改变了 阴道微生物植物群增加炎症或激活潜在的HIV宿主 细胞，增强传输。研究了杀微生物剂对 阴道植物群对微生物组几乎没有显着影响，但他们使用传统的 培养技术使用分子、非培养技术的最新研究 表明，包括阴道在内的许多人体微生物环境中的植物群， 比以前认识到的要复杂得多， 技术只能检测到环境中的一小部分微生物。我们提出 使用这些新的文化独立的技术来探索假设， 杀微生物剂改变阴道微生物组的方式可能会增强艾滋病毒 通过这些特定目的传播：1）之前和之后检查阴道微生物植物群 在对壬苯醇醚-9（N-9）的CONRAD重复1期研究中应用杀微生物剂后， 硫酸纤维素（CS）和安慰剂，使用Affyphylchip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1期研究中使用微生物cDNA测序的应用，以及3）检查 康瑞德应用杀微生物剂前后的微生物种类组成 使用PhyloChip和直接16 S rRNA基因失败的CS 3期研究 测序我们建议从最初的R21阶段过渡到 R33阶段的项目是证明使用杀微生物剂会导致 根据PhyloChip评估，阴道植物群发生显著变化。确定 杀微生物剂的应用是否与阴道微生物组的变化有关， 可能会增加艾滋病毒的传播将有助于了解以前的失败， 这将有助于未来的杀微生物剂开发工作，因为如果有害的话， 阴道植物群的变化与杀微生物剂的使用有关， 发展努力需要采取谨慎措施，避免产生潜在的有害影响， 阴道微生物组的变化。

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.