title: Cytomegalovirus antiviral resistance associated with treatment induced UL97 (protein kinase) and UL54 (DNA polymerase) mutations.
abstract: HCMV-related illness due to infections with antiviral resistant virus was verified by phenotypic and genotypic assays in 17% (8/47) of high-risk immunocompromised Australian patients. Selective PCR-sequencing of UL97 (protein kinase; PK) and UL54 (DNA polymerase; DNApol) regions important for antiviral sensitivity, identified the majority (6/8) of resistant strains through detection of mutations known to confer antiviral resistance. Additionally, eight UL54 (DNApol) mutations (N408K, T691S, A692V, S695T, L737M, A834P, V955I, and A972V) of unknown phenotype were identified in six specimens from patients with clinical evidence of antiviral resistant infections. One isolate was resistant to ganciclovir (GCV) and another resistant to PFA on phenotypic testing where mutations in UL97 (PK) or UL54 (DNApol) were not detected, suggesting a loss of correlation between phenotype and genotype. Selective PCR-sequencing of UL97 (PK) and UL54 (DNApol) provided rapid and comprehensive results, but missed some resistance detected by phenotypic assays. A combination of phenotypic and genotypic assays is recommended for complete analysis of CMV antiviral resistance, as well as further definition of the clinical relationship between novel UL54 (DNApol) mutations and antiviral resistance.
authors.affiliation: Virology Division, Department of Microbiology, SEALS, Prince of Wales Hospital, Randwick, and School of Medicial Sciences, University of New South Wales, Kensington, Australia.
authors.forename: G M
authors.initials: GM
authors.lastname: Scott
authors.forename: M A
authors.initials: MA
authors.lastname: Isaacs
authors.forename: F
authors.initials: F
authors.lastname: Zeng
authors.forename: A M
authors.initials: AM
authors.lastname: Kesson
authors.forename: W D
authors.initials: WD
authors.lastname: Rawlinson
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001315:Australia; D001388:Aziridines / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000821:virology*; D004279:DNA, Viral / Q000737:chemistry / Q000302:isolation & purification; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000502:physiology; D024882:Drug Resistance, Viral / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D016867:Immunocompromised Host; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000502:physiology; D017422:Sequence Analysis, DNA; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D001388:Aziridines; D004279:DNA, Viral; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; C479119:polyfunctional aziridine; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D015774:Ganciclovir