Contrasting drug resistance phenotypes resulting from cytomegalovirus DNA polymerase mutations at the same exonuclease locus

Background: Diverse mutations in the cytomegalovirus (CMV) DNA polymerase (pol) gene confer resistance to one or more of the antiviral drugs ganciclovir, foscarnet or cidofovir. The levels of resistance conferred by specific mutations are variable, ranging from insignificant resistance to triple-drug resistance. Objectives: Three pol mutations, I521T, P522A and P522L, detected in patients who received antiviral therapy for CMV infection, were studied by recombinant phenotyping to characterize their associated drug resistance. Study design: The individual mutations were transferred by homologous recombination into a reference CMV strain modified with a reporter gene and the drug concentrations required to reduce the reporter signal by 50% (IC50) were determined. Results: The mutations I521T and P522A each conferred 3- to 4-fold increases in IC50 to both ganciclovir and cidofovir, while mutation P522L conferred no significant resistance to either drug. None of these mutations conferred foscarnet resistance. Conclusions: The resistance phenotypes of mutations I521T and P522A are as predicted from the known mutation P522S, but divergent results with P522L indicate that different amino acid substitutions at the same position may not have the same effect on drug resistance. New mutations must be individually validated for proper interpretation of genotypic resistance testing.