Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci.
Acycloguanosine [9-(2-hydroxyethoxymethyl)guanine; acyclo-Guo] is a potent inhibitor of herpes simplex viruses (HSV); it is selectively phosphorylated in virus-infected cells. In order to define those viral functions that may mediate resistance to acyclo-Guo, the drug sensitivities of temperature-sensitive (ts) and phosphonoacetic acetic acid (PAA)-resistant mutants of HSV-1 and HSV-2 have been determined. Two distinct viral genetic loci are independently associated with acyclo-Guo resistance. Mutations resulting in diminished thymidine kinase activity are associated with resistance to inhibition by acyclo-Guo. Several PAA-resistant viruses that express wild-type levels of thymidine kinase activity are also resistant to acyclo-Guo. This suggests the importance of the viral DNA polymerase region in mediating acyclo-Guo resistance and is consistent with a close relationship between the PAAr mutation site and the AGGr locus. When wild-type HSV-1 is serially propagated under the selective pressure of acyclo-Guo, rapid emergence of resistant virus occurs, accompanied by the simultaneous appearance of thymidine kinase-deficient progeny.
D000998:Antiviral Agents / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004352:Drug Resistance, Microbial; D005796:Genes; D005814:Genes, Viral; D009154:Mutation; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D010746:Phosphonoacetic Acid