Use of herpes simplex virus thymidine kinase to improve the antiviral activity of zidovudine.
Many antiviral drugs must be metabolized to their active form by cellular enzymes. Their antiviral activity may therefore be limited by an inefficient metabolism, leading to low intracellular concentration of the active form or to the accumulation of toxic intermediate metabolites. Gene transfer might be used to overcome such limitations by transducing a gene able to increase intracellular drug metabolism. To prove such 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 human cells, the rate-limiting step for AZT phosphorylation is catalyzed by the thymidylate kinase. We thus tested the capacity of herpes simplex virus type 1 thymidine kinase, which possesses a thymidylate kinase activity, to improve AZT metabolism and antiviral activity. Our results show enhanced AZT phosphorylation in HSV-1 TK-expressing lymphoid and monoblastoid cells, which correlated with significantly improved antiviral activity against different strains of HIV-1. The antiviral activity 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.
Guettari
N
N
Centre National de la Recherche Scientifique, ERS 107, Hôpital de la Pitié-Salpêtrière, 83, Boulevard de l'hôpital, Paris Cedex 13, 75651, France.
Loubière
L
L
Brisson
E
E
Klatzmann
D
D
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000378:metabolism*; D002478:Cells, Cultured; D017245:Foscarnet / Q000008:administration & dosage; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D015215:Zidovudine / Q000008:administration & dosage* / Q000378:metabolism*
D019380:Anti-HIV Agents; D017245:Foscarnet; D015215:Zidovudine; D013937:Thymidine Kinase