title: Single and multiple mutations in the human cytomegalovirus UL97 gene and their relationship to the enzymatic activity of UL97 kinase for ganciclovir phosphorylation.
abstract: In this study we determined that the double mutant M460V/D605E in the UL97 gene of an HCMV isolate from an immunocompromised patient (MMT isolate) is related to resistance to ganciclovir (GCV) therapy. Our results suggest that the aspartic acid-to-glutamic acid substitution at codon 605 may be associated with a natural polymorphism of the UL97 gene, and not with positive selection pressure exerted by the antiviral drug. We also determined that GCV resistance due to the M460V mutation in the HCMV UL97 gene is not offset by a second mutation (D605E) at codon 605. Furthermore, we showed that when the two mutations related to GCV resistance were simultaneously detected in the same HCMV construct, virus-drug resistance might be enhanced in comparison to that of the single mutants studied separately. To our knowledge for the first time, seven of 12 amino acid changes (F102L, D118V, M330T, T400A, R507P and C511R and I533V) in the UL97 gene of an isolate are herein reported.
authors.affiliation: Centro de Referencia para el SIDA, Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina-Universidad de Buenos Aires, Paraguay 2155, piso 11, (C1121ABG)-CABA, Argentina. ssp@fibertel.com.ar
authors.forename: Silvia I
authors.initials: SI
authors.lastname: Sanchez Puch
authors.forename: Verónica L
authors.initials: VL
authors.lastname: Mathet
authors.forename: Margarita
authors.initials: M
authors.lastname: Porta
authors.forename: María L
authors.initials: ML
authors.lastname: Cuestas
authors.forename: José R
authors.initials: JR
authors.lastname: Oubiña
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Videla
authors.forename: Horacio E
authors.initials: HE
authors.lastname: Salomón
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics; D005347:Fibroblasts / Q000821:virology; D015774:Ganciclovir / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D016867:Immunocompromised Host; D009154:Mutation; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic
chemical_list: D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir