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

微生物组驱动的抗逆转录病毒生物降解机制及其对病毒库的影响

• 批准号: 10150302
• 负责人: Nichole Rose Klatt
• 金额: $ 24.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10150302
• 关键词: Mechanisms; microbiome; driven; antiretroviral; biodegradation

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.

项目概要 药物微生物组学是一个非常新颖的研究领域，它评估微生物组对药物的影响 代谢和药代动力学。我们最近证明微生物群可以代谢抗逆转录病毒药物 药物，导致替诺福韦预防 HIV 感染的功效下降。我们接下来寻求识别 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 降低药物功效，从而促进 HIV 和 SIV 储存活性。 在这里，我们将使用一种高度新颖的系统来评估体内微生物群的药物代谢。我们将标记 抗逆转录病毒药物 13C 并给予非人类灵长类动物，并使用 DNA 稳定来识别细菌 小肠、大肠和粪便中的同位素探测。一旦确定了药物代谢细菌，我们 将量化他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识别 参与药物代谢的细菌蛋白。此外，我们将评估两者之间的关系 这些动物的微生物组和 SIV 储存库，以及评估 HIV 储存库相对于 HIV感染者的微生物组。 对于阐明哪些微生物群可能导致药物减少具有非常重要的意义 可用性和病毒库。事实上，抗逆转录病毒药物的药代动力学相对于 微生物群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并减少艾滋病毒储存库。