Emergence of resistance to acyclovir and penciclovir in varicella-zoster virus and genetic analysis of acyclovir-resistant variants

Abstract

We have characterized the differential actions of acyclovir and penciclovir against varicella-zoster virus (VZV) in cell culture by comparing the frequency of appearance of resistant viruses followed by their characterization. Cells were infected with cell-free virus and the cultures were successively treated with increasing concentrations of acyclovir or penciclovir. Drug-resistant viruses were selected in the presence of 6 microg/ml of acyclovir or penciclovir. The emergence frequency of resistant viruses was significantly higher following acyclovir exposure than following penciclovir exposure (Fisher's exact test, P<0.0001), possibly reflecting virus growth differences under these experimental conditions. Based on antiviral drug susceptibility and thymidine kinase (TK) activity assays, 11 acyclovir-resistant variants from seven experiments using three virus strains (Kawaguchi strain, Oka varicella vaccine strain and a clinical isolate from a zoster patient) were found to be TK-deficient. Sequence analysis of TK-deficient variants of the Kawaguchi strain revealed deletions that caused frameshifts, resulting in premature termination in the TK gene.