Hypersusceptibility of Human Cytomegalovirus to Foscarnet Induced by Mutations in Helices K and P of the Viral DNA Polymerase

Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to foscarnet (respective mean 50% effective concentrations [EC 50 ] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling analysis suggested that both mutations favor the closed conformation of the enzyme to which foscarnet binds with a higher affinity.