Point mutations in the varicella-zoster virus DNA polymerase gene confers resistance to foscarnet and slow growth phenotype.

Seven independent laboratory mutants were derived from seven distinct wild-type varicella-zoster virus (VZV) isolates after exposure to increasing concentrations of foscarnet (PFA) and were found to be resistant to this drug. Single base changes resulting in amino acid substitutions were observed in the nucleotide sequence of the DNA polymerase gene of each PFA-resistant mutant. The mutations were found to occur within the domain II (Arg-665 --> Gly for strains vrMOR and vrVER; Val-666 --> Leu for vrLEB; Gln-692 --> Arg for vrOLI) and domain III (Arg-806 --> Ser for vrABD; Leu-809 --> Ser for vrALI and vrCHA) of DNA polymerase gene. In addition, the PFA-resistant mutants exhibited a phenotype characterized by slow growth, the strains showing a marked delay in immediate-early antigen plaque formation compared with the wild-type VZV from which they were derived. These results may have implications for successful isolation and characterization of PFA-resistant strains from clinical samples containing mixed viral populations.