Altered substrate specificity of herpes simplex virus thymidine kinase confers acyclovir-resistance

Abstract

Acyclovir (9-[2-hydroxyethoxymethyl]guanine or ACV) is a nucleoside analogue with considerable potential for the treatment of herpes simplex virus (HSV) infections in man^1,2. Two virus-coded enzymes are important in the mechanism of action of this drug: thymidine kinase (TK) which initiates its activation by converting it to the monophosphate³ and DNA polymerase whose action is inhibited by ACV triphosphate⁴. Changes in either gene may confer resistance^5–7, but all reported mutations in the TK gene have resulted in failure of the resistant virus to induce appreciable levels of the enzyme. Such TK⁻ mutants arise readily in tissue culture systems^8,9 where the enzyme is non-essential for virus replication¹⁰, but in animals they show considerably reduced pathogenicity and neurovirulence^7,11–14. We now describe the isolation of a resistant mutant which induces a TK of altered substrate specificity and we show that this virus retains pathogenicity for mice with only a slight attenuation of neurovirulence.