ACYCLOVIR-RESISTANT VARICELLA-ZOSTER VIRUS - PHENOTYPIC AND GENETIC-CHARACTERIZATION

A man with acquired immunodeficiency syndrome (AIDS) developed tester of the right arm which was resistant clinically to acyclovir. Varicell a-zoster virus (VZV) was cultured from a skin biopsy performed at the beginning of acyclovir therapy (isolate 1) and after its failure (isol ate 2). The emergence of acyclovir resistance during treatment was inv estigated by developing a simple and rapid drug sensitivity assay base d on the plaque reduction reference method. This late-antigen synthesi s reduction assay involved serial dilutions of cell-associated virus. The 50% inhibitory concentration (IC50) of acyclovir was 16 +/- 7.5 mu M for the susceptible reference strain OKA, in agreement with publish ed data. The acyclovir IC50 increased from 6.5 mu M for isolate 1 to 1 00 mu M for isolate 2. In comparison with the sequence of isolate 1, i solate 2 had a single mutation consisting of a C to T change at positi on 907 of the thymidine kinase gene, which changed a glutamine codon i nto a stop codon at position 303 of the thymidine kinase protein. Thes e results show the emergence of acyclovir resistance through a single previously undescribed mutation in the thymidine kinase gene, and conf irm the heterogeneity of mutations inducing acyclovir resistance. (C) 1998 Wiley-Liss, Inc.