[Genetically controlled pharmacomodulation: application to the treatment of HIV infection]

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 unfficient cellular metabolism of AZT which leads to the intracellular accumulation of AZT monophosphate. We tested a possible enhancement of this metabolism with the HSV1 thymidine kinase, an enzyme that also possesses a good thymidilate kinase activity. We show that, compared to parental 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 pharmacomodulation.