Differential mutation patterns in thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 clones passaged in the presence of acyclovir or penciclovir

A total of 21 clones of acyclovir (ACV)-resistant (ACV) herpes simplex virus type 1 (HSV-1) and 23 clones of penciclovir (PCV)-resistant (PCVr) HSV-1, emerging during serial passages in the presence of ACV or PCV, were isolated under conditions excluding contamination of resistant mutants in the starting virus culture, and their mutations in the thymidine kinase (TK) and DNA polymerase (DNA Pol) genes were analyzed comparatively. Mutations in the TK genes from ACV(r) mutants consisted of 50% single nucleotide substitutions and 50% frameshift mutations, while the corresponding figures for the PCVr mutants were 4 and 96%, respectively (P<0.001). Eight of the 21 ACV(r) clones, but none of the 23 PCVr clones, had mutations in DNA Pol. Only nucleotide substitution(s) could be detected in the DNA Pol gene, as the gene is essential for virus replication. Therefore, the results for the DNA Pol mutants are concordant with those for the TK mutants in that a single nucleotide substitution was commonly observed in the ACV(r), but not in the PCVr, mutants. These results clearly point to differential mutation patterns between ACV(r) and PCVr HSV-1 clones.