Mutations in the herpes simplex virus DNA polymerase gene can confer resistance to 9-beta-D-arabinofuranosyladenine.
Mutants of herpes simplex virus type 1 resistant to the antiviral drug 9-beta-D-arabinofuranosyladenine (araA) have been 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 four previously described PAA-resistant mutants, two exhibited substantial araA resistance. The araA resistance phenotype of one of these mutants, PAAr5, has been 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. These genetic and biochemical data indicate that the herpes simplex virus DNA polymerase gene is a locus which, when mutated, can confer resistance to araA and thus that the herpes simplex virus DNA polymerase is a target for this antiviral drug.
D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004352:Drug Resistance, Microbial; D005814:Genes, Viral; D009154:Mutation; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D014740:Vidarabine / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics*
D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase; D014740:Vidarabine; D010746:Phosphonoacetic Acid