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

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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.