Viral DNA Polymerase Mutations Associated with Drug Resistance in Human Cytomegalovirus

Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.