Penciclovir-Resistance Mutations in the Herpes Simplex Virus DNA Polymerase Gene

Abstract

Penciclovir is the active form of the orally available prodrug famciclovir, which is entering clinical use for herpesvirus infections. Like aciclovir, penciclovir is an acyclic guanosine analogue that is phosphorylated by viral thymidine kinase and whose triphosphate can inhibit viral DNA polymerase. We tested several well-characterized herpes simplex virus mutants with aciclovir-resistance mutations in the viral DNA polymerase gene for altered sensitivity to penciclovir. The mutants varied in their susceptibilities to penciclovir with one exhibiting 2-fold hypersensitivity, one marginal resistance and three about 3-fold resistance. Marker rescue and DNA sequencing analyses mapped the penciclovir-resistance mutation of one mutant, AraA r7, to a single base change that alters a glycine to a cysteine at residue 841 within conserved region III of α-like DNA polymerases. The results have implications for the mechanism of selective action of penciclovir, for the potential for development of resistance in the clinic, and for the substrate recognition properties of herpes simplex virus DNA polymerase.