This project will study mechanisms of resistance to antiretroviral therapy and treatment strategies to further improve chemotherapy effectiveness. Long-term goals are to improve individualized antiretroviral treatment strategies, minimize risk of antiretroviral drug failure, and maximize chance of lifelong suppression or cure of HIV-1 infection.
Specific aims are: 1. To further characterize mechanisms of drug failure, including virus resistance, drug transporters, and other mechanisms. (A) Characterization of lymphocyte drug transporter expression and function, as well as its modulation by immune activation/differentiation, HIV infection, and antiretroviral drug exposure. It will be characterized whether ATP-binding cassette transporters for PI-efflux (Pgp (ABCB 1, MDR1), MRP 1 (ABCC1), and/or MRP2 (ABCC2)), nucleoside influx (OAT1, OAT3, and OAT4, CNT-1 and-2, and ENTs), and nucleoside efflux (MRP4 (ABCC4), MRP5 (ABCC5) are expressed and functional in lymphocytes. Ex vivo studies of the effect of cell activation/differentiation on transporters, and of HIV infection on Pgp expression, are proposed. In addition, ex vivo and in vivo pilot studies will assess effects of antiretrovirals on transporters. (B) Comprehensive, prospective evaluation of multiple potential mechanisms of drug failure in vivo. A prospective cohort will be followed to confirm and extend results showing that resistant virus is infrequently detected at failure of regimens including a """"""""boosted PI"""""""". A comprehensive evaluation of multiple mechanisms of initiation of failure will be undertaken to evaluate hypotheses involving adherence / blood levels of drugs, changes in expression / function of cellular drug transporters predicted to have a net effect of lowering intracellular drug concentrations, as well as virus-related mechanisms including escape from immune selection. 2. To further study the biology of HIV's latent reservoir during successfully suppressive therapy by identifying associations between size of the latent reservoir and other factors. The variation across individuals in size of the latent reservoir during apparently equally successful therapy will be correlated with variation of another factor. Factors to be studied include differences in the number of proviral DNA copies, levels of Pgp expression/function, differences in expression of apobec 3G that may cause variation in the proportion of integrated viruses that are replication-competent. It will also be tested whether decreased apoptosis or increased virus replicative capacity are associated with a larger reservoir. ? ? ?
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