Mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene can confer altered drug sensitivities

Two herpes simplex virus mutants containing mutated residues within the conserved fro III motif of the polymerase gene were previously shown to be defective in 3'-5' exonuclease activity and exhibited extremely high mutation frequencies. In this study, we have shown that these mutants also exhibited higher resistance to phosphonoacetic acid and sensitivity to aphidicolin and all nucleoside analogs tested, including acyclovir and gancicolvir, compared to wild-type virus. Marker transfer experiments and sequencing analyses demonstrated that these altered phenotypes were the result of mutations within the fro III motif. The data indicate that, aside from leading to exonuclease deficiency,mutations in the fro III motif may also affect interaction of nucleoside triphosphates with the catalytic sites of polymerase activity, (C) 1998 Academic Press.