GENETICALLY CONTROLLED PHARMACOMODULATION FOR HIV GENE-THERAPY

AZT is an inhibitor of HIV reverse transcriptase which active form is AZT-triphosphate. Its clinical efficacy is limited by its toxicity and the emergence of mutant resistant viruses This might be due to an unf ficient cellular metabolism of AZT which leads to the intracellular ac cumulation of AZT monophosphate. We tested a possible enhancement of t his metabolism with the HSV1 thymidine kinase, an enzyme that also pos sesses a good thymidilate kinase activity. We show that, compared to p arental cells, the proportion of AZT triphosphate is increased 3 fold in HSV1-TK expressing cells, and that inhibition of HIV replication in these cells requires 3 to 10 fold less AZT This observation forms the basis for a new gene therapy strategy named genetically, controlled p harmacomodulation.