Isolation of drug resistant mutants of varicella-zoster virus: cross resistance of acyclovir resistant mutants with phosphonoacetic acid and bromodeoxyuridine.
Mutants of Varicella-Zoster Virus (VZV) which are resistant to phosphonoacetic acid (PAA), bromodeoxyuridine (BuDR), and acyclovir (ACV) were obtained by serial passages of VZV with increasing concentrations of these drugs. A PAA-resistant mutant and a BuDR-resistant mutant were found also to be resistant to ACV. Five of 8 ACV-resistant mutants acquired resistance to PAA, but none acquired resistance to BuDR. The BuDR-resistant mutant did not induce viral thymidine kinase (TK) activity, but all the ACV-resistant mutants selected in ACV showed viral TK activity which was suppressed with anti-VZV serum and had almost the same electrophoretic mobility as that of the parent strain on polyacrylamide gel electrophoresis in non-denaturing conditions. However, in competitive TK assay with ACV, 2 of 8 ACV-resistant mutants showed no change of phosphorylation of radioactive thymidine, while the other 6 showed decreased phosphorylation of radioactive thymidine. It was suggested that TK induced by the former 2 ACV-resistant mutants had lost affinity to ACV, and so the mutants could grow in the presence of ACV. Thus of the 8 ACV-resistant mutants selected in ACV, 2 were sensitive to PAA with altered TK activity, 5 were resistant to PAA with unaltered TK activity, and 1 was sensitive to PAA with unaltered TK activity, and may have altered DNA polymerase activity to ACV, retaining sensitivity to PAA. These results suggest that resistance of VZV to ACV results from alterations in the virus-specified TK or DNA polymerase, as demonstrated in HSV resistant to ACV.
D000212:Acyclovir / Q000378:metabolism / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004790:Enzyme Induction; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010746:Phosphonoacetic Acid / Q000494:pharmacology*; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000378:metabolism
D009943:Organophosphorus Compounds; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D001973:Bromodeoxyuridine; D010746:Phosphonoacetic Acid; D000212:Acyclovir