Mutations in the herpes simplex virus DNA polymerase gene can confer resistance to 9-beta-D-arabinofuranosyladenine

Abstract

Mutants of herpes simplex virus type 1 resistant to the antiviral drug 9-.beta.-D-arabinofuranosyladenine (araA) were isolated and characterized. AraA-resistant mutants can be isolated readily and appear at an appreciable frequency in low-passage stocks of wild-type virus. Of 13 newly isolated mutants, at least 11 were also resistant to phosphonoacetic acid (PAA). Of 4 previously described PAA-resistant mutants, 2 exhibited substantial araA resistance. The araA resistance phenotype of 1 of these mutants, PAAr5, was mapped to the HpaI-B fragment of herpes simplex virus DNA by marker transfer and araA resistance behaved in marker transfer experiments as if it were closely linked to PAA resistance, a recognized marker for the viral DNA polymerase locus. PAAr5 induced viral DNA polymerase activity which was much less susceptible to inhibition by the triphosphate derivative of araA than was wild-type DNA polymerase. The herpes simplex virus DNA polymerase gene apparently is a locus which, when mutated, can confer resistance to araA and thus the herpes simplex virus DNA polymerase is a target for this antiviral drug.