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

We have characterized the differential actions of acyclovir and penciclovir against varicella-zoster virus (VZV) in cell culture by comparing the freq uency of appearance of resistant viruses followed by their characterization . Cells were infected with cell-free virus and the cultures were successive ly treated with increasing concentrations of acyclovir or penciclovir. Drug -resistant viruses were selected in the presence of 6 mu g/ml of acyclovir or penciclovir. The emergence frequency of resistant viruses was significan tly higher following acyclovir exposure than following penciclovir exposure (Fisher's exact test, P<0.0001), possibly reflecting virus growth differen ces under these experimental conditions. Based on antiviral drug susceptibi lity and thymidine kinase (TK) activity assays, 11 acyclovir-resistant vari ants from seven experiments using three virus strains (Kawaguchi strain, Ok a varicella vaccine strain and a clinical isolate from a tester patient) we re 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. (C) 1999 Elsevier Science B.V. All rights reserved.