Open AccessCyclopropavir Susceptibility of Cytomegalovirus DNA Polymerase Mutants Selected after Antiviral Drug Exposure
Author(s) -
Sunwen Chou,
Gail I. Marousek,
Terry L. Bowlin
Publication year - 2012
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.05559-11
Subject(s) - cidofovir , foscarnet , biology , mutant , dna polymerase , ganciclovir , virology , exonuclease , microbiology and biotechnology , polymerase , mutation , human cytomegalovirus , dna , virus , gene , genetics
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 (EC50 ) increases of 3- to 13-fold. CPV EC50 values against severalpol mutants were increased about 2-fold by adding UL97 mutation C592G. Propagation of a CMV exonuclease mutant under CPV selected forpol 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 EC50 , was detected. Unlike GCV and CDV, exonuclease mutations are not a preferred mechanism of CPV resistance, but mutations in and nearpol region III may confer CPV resistance by affecting its recognition as an incoming base for DNA polymerization.