Mechanisms of microbiome-driven antiretroviral biodegradation and effects on viral reservoir

项目总结 药物微生物学是一个非常新的研究领域，它评估微生物组对药物的影响 代谢和药代动力学。我们最近证明了微生物群可以代谢抗逆转录病毒。 药物，导致替诺福韦作为艾滋病毒感染预防药物的疗效降低。接下来我们要找出 来自胃肠道的微生物群，在体内代谢抗逆转录病毒药物，并可能有助于 降低药物疗效，从而导致艾滋病毒和SIV宿主活动。 在这里，我们将使用一种非常新颖的系统来评估体内微生物群的药物代谢。我们会贴上标签 含13C的抗逆转录病毒药物和对非人类灵长类动物的给药，并使用DNA稳定鉴定细菌 小肠、大肠和粪便中的同位素探测。一旦鉴定出药物代谢细菌，我们 将量化它们在体外代谢每种药物的能力，并将使用新的蛋白质组学方法来鉴定 参与药物代谢的细菌蛋白质。此外，我们将评估两国之间的关系 微生物群和SIV储存库，以及评估相对于 HIV感染者体内的微生物群。 阐明哪些微生物区系可能导致药物减少具有重要意义。 可获得性和病毒库。事实上，抗逆转录病毒药物的药代动力学相对于 微生物区系及其背后的机制可能会指导未来改进的治疗干预措施， 旨在提高抗逆转录病毒药物的疗效，减少艾滋病毒携带者。

PROJECT SUMMARY Pharmacomicrobiomics is a highly novel field of study which assesses the impact of the microbiome on drug metabolism and pharmacokinetics. We recently demonstrated that microbiota can metabolize antiretroviral drugs, leading to decreased efficacy of tenofovir as a preventative for HIV infection. We next seek to identify microbiota from the gastrointestinal tract that metabolize antiretroviral drugs in vivo, and could contribute to decreased drug efficacy and thus contribute to HIV and SIV reservoir activity. Here we will use a highly novel system to assess drug metabolism by microbiota in vivo. We will label antiretroviral drugs with 13C and administer to non-human primates, and identify bacteria using DNA stable isotope probing in small intestine, large intestine and feces. Once drug metabolizing bacteria are identified, we will quantify their ability to metabolize each drug in vitro, and will use novel proteomic approaches to identify bacterial proteins involved in drug metabolism. Further, we will assess the relationship between the microbiome and the SIV reservoir in these animals, as well as assess the HIV reservoir relative to the microbiome in HIV-infected patients. There are highly significant implications for elucidating which microbiota may contribute to decreased drug availability and the viral reservoir. Indeed, the pharmacokinetics of antiretroviral drugs relative to the microbiota, and the mechanisms underlying this, may guide improved therapeutic interventions in the future, aimed at improving efficacy of antiretroviral drugs and decreasing the HIV reservoir.