The overall aim of this proposal is to study the biochemical pharmacology of anti-human immunodeficiency virus type 1 (HIV-1) compounds; this includes their mechanism of action, resistance, and toxicity. The current compounds of interest will be anti-HIV-1 nucleoside analogs with a special focus on beta-L(-)dideoxynucleosides. The focus of the proposed studies is the elucidation of key host cellular biochemical determinants that are shared by all anti-HIV-1 nucleoside analogs and the interaction of beta-D(+) and beta-L(-)dideoxynucleoside analogs with these determinants. The following Specific Aims are based on original findings in this laboratory. I. Characterization of cytoplasmic DNA exonucleases, TREx-1 and TREx-2, that may constitute a significant mechanism of viral sensitivity to anti-HIV-1 nucleoside analogs. A. Substate specificity and cellular behavior of TREx-1 and TREx-2 B. Inducibility and regulation of these two exonculeases by HIV-1 and/or anti-HIV-1 nucleoside analogs. C. Role of these two exonuclease enzymatic activities in the sensitivity of HIV-1 to anti-HIV-1 nucleoside analogs and the synergistic antiviral interaction of beta-L(-)dideoxycytidine analogs with d4T. II. Characterization of a mitochondria) deoxynucleoside triphosphate (dNTP) carrier that maybe a significant determinant in the toxicity of anti-HIV-1 nucleoside analogs to mitochondrial function. A. Substrate and inhibitor specificity of the dNTP carrier. B. Molecular characterization of the mitochondrial dNTP carrier with a special focus on a 29 kDa protein (p29). C. Establish the role of p29 as a member of the dNTP carrier and its role in the toxicity of nucleoside analogs against mitochondrial DNA synthesis.
Both Specific Aims are to address the role of two novel host factors in the determination of the efficiency of nucleoside analogs against HIV-1. The information obtained will be useful for our understanding the differences in the effectiveness of anti-HIV-1 nucleoside analogs among different individuals and in a given patient through a period of treatment.
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