Effects of Aging and Inflammation on Intracellular Nucleoside Reverse Transcriptase Inhibitor Pharmacology in the WIHS Cohort

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PROJECT ABSTRACT This application proposes to determine if age drives changes in intracellular pharmacology, and identify clinical and immunologic factors that affect the age-pharmacology relationship by testing the hypothesis that increased cellular activation and inflammation that occurs with aging will decrease intracellular nucleos(t)ide reverse transcriptase inhibitor (NRTI) intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations in HIV-infected women, resulting in a decreased IM:EN ratio. We aim to: (1) quantify and compare intracellular IM and EN concentrations in older (current age ≥60 years) vs. younger (current age ≤5 years) HIV-infected women receiving tenofovir (TFV) and emtricitabine (FTC) enrolled in the WIHS, as well as compare intracellular IM and EN concentrations longitudinally in older (current age ≥60 years) vs. younger (current age ≤45years) on the same regimen; (2) determine if IL-6 and sCD163 concentrations in plasma and/or the presence of senescent cells are associated with changes in the IM:EN ratio; and (3) quantify and compare intracellular IM and EN concentrations in HIV-infected women enrolled in the Women's Interagency HIV Study receiving tenofovir concurrently with previously measured urinary biomarkers, and compare IM and EN concentrations in age- and regimen-matched women who experienced toxicity vs. those who did not. The proposed study will build off the previous pharmacology and drug-related toxicity research conducted in the WIHS, address questions about the pharmacology of aging in women, and provide preliminary data for R01-level prospective investigations into the mechanism and clinical ramifications of altered IM:EN ratios in treated HIV-infected women and men.