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 con centrations 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 m utant. The mutations were found to occur within the domain II (Arg-665 --> Gly for strains vrMOR and vrVER; Val-666 --> Leu for vrLEB; GIn-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 mut ants exhibited a phenotype characterized by slow growth, the strains showin g a marked delay in immediate-early antigen plaque formation compared with the wild-type VZV from which they were derived. These results may have impl ications for successful isolation and characterization of PFA-resistant str ains from clinical samples containing mixed viral populations. (C) 1999 Wil ey-Liss, Inc.