USE OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE TO IMPROVE THE ANTIVIRALACTIVITY OF ZIDOVUDINE

Many antiviral drugs must be metabolized to their active form by cellu lar enzymes. Their antiviral activity may therefore be limited by an i nefficient metabolism, leading to low intracellular concentration of t he active form or to the accumulation of toxic intermediate metabolite s. Gene transfer might be used to overcome such limitations by transdu cing a gene able to increase intracellular drug metabolism. To prove s uch a concept, we chose the well-studied paradigm of zidovudine (AZT) metabolism and anti-HIV activity. AZT-triphosphate is the active form of AZT, acting through inhibition of HIV reverse transcription. In hum an cells, the rate-limiting step for AZT phosphorylation is catalyzed by the thymidylate kinase. We thus tested the capacity of herpes simpl ex virus type 1 thymidine kinase, which possesses a thymidylate kinase activity, to improve AZT metabolism and antiviral activity. Our resul ts show enhanced AZT phosphorylation in HSV-1 TK-expressing lymphoid a nd monoblastoid cells, which correlated with significantly improved an tiviral activity against different strains of HIV-1, The antiviral act ivity of Foscarnet, another reverse transcriptase inhibitor that does not require phosphorylation, remained unchanged. These results suggest that gene transfer might be envisioned for genetic pharmacomodulation of antiviral drugs. (C) 1997 Academic Press.