Acyclovir-resistant varicella-zoster virus: phenotypic and genetic characterization.
A man with acquired immunodeficiency syndrome (AIDS) developed zoster of the right arm which was resistant clinically to acyclovir. Varicella-zoster virus (VZV) was cultured from a skin biopsy performed at the beginning of acyclovir therapy (isolate 1) and after its failure (isolate 2). The emergence of acyclovir resistance during treatment was investigated by developing a simple and rapid drug sensitivity assay based on the plaque reduction reference method. This late-antigen synthesis reduction assay involved serial dilutions of cell-associated virus. The 50% inhibitory concentration (IC50) of acyclovir was 16 +/- 7.5 microM for the susceptible reference strain OKA, in agreement with published data. The acyclovir IC50 increased from 6.5 microM for isolate 1 to 100 microM for isolate 2. In comparison with the sequence of isolate 1, isolate 2 had a single mutation consisting of a C to T change at position 907 of the thymidine kinase gene, which changed a glutamine codon into a stop codon at position 303 of the thymidine kinase protein. These results show the emergence of acyclovir resistance through a single previously undescribed mutation in the thymidine kinase gene, and confirm the heterogeneity of mutations inducing acyclovir resistance.
Fillet
A M
AM
Virology Department, Pitié-Salpêtrière Hospital, Paris, France.
Dumont
B
B
Caumes
E
E
Visse
B
B
Agut
H
H
Bricaire
F
F
Huraux
J M
JM
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000821:virology*; D000212:Acyclovir / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D005814:Genes, Viral; D006562:Herpes Zoster / Q000188:drug therapy / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013937:Thymidine Kinase / Q000235:genetics; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D013937:Thymidine Kinase; D000212:Acyclovir