The long range goal of this research project is to understand the intracellular pharmacology of antiretroviral drugs used against HIV. Specifically, the in vivo effect of ribavirin on the phosphorylation process of zidovudine (ZDV) in HIV-HCV (Hepatitis C virus) co-infected patients. The central hypothesis to be tested is that REBETRON (ribavirin + interferon alpha) will antagonize in vivo ZDV, diminishing the formation of ZDV intracellular metabolites (ZDV-MP and ZDV-TP), by increasing thymidine triphosphate (dTTP, endogenous competitor for HIV reverse transcriptase) intracellular concentrations which inhibits thymidine kinase 1 and decreases TK1 m RNA expresion. These events may affect HIV clinical outcomes in HIV-HCV co-infected patients.

This pilot project focuses on the molecular aspects of ZDV metabolism before and after Rebetron treatment in HIV-HCV co-infected patients. Studies will be performed to determine if changes in the intracellular concentration of ZDV-MP and ZDV-TP are caused by altered expression of the tThymidine kinase gene (TK1) after Rebetron treatment. In vitro changes have been observed in the metabolism of ZDV in cells treated with ribarin, but in vivo information is not currently available. Thus, this study will provide unique information to understand the in vivo pharmacological drug-drug interactions at the intracellular level. This information will serve as a stepping stone to provide a more rational basis for dosing HIV-HCV co-infected patients in the era of HAART therapy.