Isolation of foscarnet-resistant human cytomegalovirus patterns of resistance and sensitivity to other antiviral drugs

Abstract

Investigations of mutants of human cytomegalovirus (CMV) that are resistant to foscarnet could shed light on mechanisms of selective drug action and features of drug resistance that may be clinically important. Preexisting foscarnet-resistant mutants could not be detected in a stock of wild-type strain AD169 at frequencies greater than 0.0025%. However, foscarnet-resistant mutants could be isolated by passage in increasing drug concentrations. Two independent mutants were shown by plaque reduction and dot-blot hybridization assays to be resistant to phosphonoacetic acid and acyclovir, sensitive to ganciclovir, vidarabine, 2'fluoro-5-iodoarabinosylcytosine, and (S)-1-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine; and hypersensitive to aphidicolin and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine. These results have implications for the mutation frequency of CMV, for the possibility that clinically important foscarnet- and acyclovir-resistant CMV infections could emerge, for possible therapies of drug-resistant virus infections, and for the role of viral DNA polymerase in mechanisms of selective action of anti-CMV drugs.