title: Cyclopropavir susceptibility of cytomegalovirus DNA polymerase mutants selected after antiviral drug exposure.
abstract: Human cytomegalovirus (CMV) UL54 DNA polymerase (pol) mutants with known patterns of resistance to current antivirals ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV) were tested for cyclopropavir (CPV) susceptibility by a standardized reporter-based yield reduction assay. Exonuclease and A987G (region V) mutations at codons commonly associated with dual GCV-CDV resistance in clinical isolates paradoxically conferred increased CPV susceptibility. Various polymerase catalytic region mutations conferring FOS resistance with variable low-grade GCV and CDV cross-resistance also conferred CPV resistance, with 50% effective concentration (EC(50)) increases of 3- to 13-fold. CPV EC(50) values against several pol mutants were increased about 2-fold by adding UL97 mutation C592G. Propagation of a CMV exonuclease mutant under CPV selected for pol mutations less often than UL97 mutations. In 21 experiments, one instance each of mutations E756D and M844V, which were shown individually to confer 3- to 4-fold increases in CPV EC(50), was detected. Unlike GCV and CDV, exonuclease mutations are not a preferred mechanism of CPV resistance, but mutations in and near pol region III may confer CPV resistance by affecting its recognition as an incoming base for DNA polymerization.
authors.affiliation: Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA. chous@ohsu.edu
authors.forename: Sunwen
authors.initials: S
authors.lastname: Chou
authors.forename: Gail
authors.initials: G
authors.lastname: Marousek
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
mesh_terms: D000469:Alkaline Phosphatase; D000998:Antiviral Agents / Q000494:pharmacology; D000077404:Cidofovir; D003521:Cyclopropanes / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000821:virology; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000187:drug effects*; D005092:Exonucleases / Q000235:genetics*; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D017930:Genes, Reporter; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology; D010641:Phenotype; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D063065:Organophosphonates; D014764:Viral Proteins; D017245:Foscarnet; D006147:Guanine; D003596:Cytosine; C495219:cyclopropavir; D004259:DNA-Directed DNA Polymerase; D005092:Exonucleases; D000469:Alkaline Phosphatase; D000077404:Cidofovir; D015774:Ganciclovir