title: Resistance of human cytomegalovirus to ganciclovir/valganciclovir: a comprehensive review of putative resistance pathways.
abstract: Human cytomegalovirus (HCMV) is a pathogen that can be life-threatening in immunocompromised individuals. Valganciclovir and its parent drug ganciclovir are currently the principle drugs used for the treatment or prevention of HCMV disease. The development of HCMV resistance to ganciclovir/valganciclovir has been documented in treated patients and is associated with the emergence of amino acid substitutions in the viral proteins pUL97, pUL54 or both. Generally, single amino acid substitutions associated with clinical resistance that alone do not confer decreased ganciclovir susceptibility in cell culture have been disregarded as causative or clinically significant. This review focuses on the analysis and mechanisms of antiviral drug resistance to HCMV. We also conducted a review of publicly available clinical and nonclinical data to construct a comprehensive list of pUL97 and pUL54 amino acid substitutions that are associated with a poor clinical response to the first line therapies ganciclovir and valganciclovir, or associated with reduced HCMV ganciclovir susceptibility in cell culture. Over 40 putative ganciclovir/valganciclovir resistance-associated substitutions were identified in this analysis. These include the commonly reported substitutions M460I/V and C592G in pUL97. There were additional substitutions that are not widely considered as ganciclovir/valganciclovir resistance-associated substitutions, including V466M in pUL97 and E315D in pUL54. Some of these ganciclovir/valganciclovir resistance-associated substitutions may confer cross-resistance to other HCMV therapies, such as cidofovir and foscarnet. Based on this review, we propose that there are more potential HCMV ganciclovir/valganciclovir resistance pathways than generally appreciated. The resulting comprehensive list of putative ganciclovir/valganciclovir resistance-associated substitutions provides a foundation for future investigations to characterize the role of specific substitutions or combinations of substitutions, which will enhance our understanding of HCMV mechanisms of ganciclovir/valganciclovir resistance and also provide insight regarding the potential for cross-resistance to other HCMV therapies.
authors.affiliation: Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: Takashi.Komatsu@fda.hhs.gov.
authors.forename: Takashi E
authors.initials: TE
authors.lastname: Komatsu
authors.affiliation: Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; Microbial Biochemistry and Genetics Section, Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pikis
authors.affiliation: Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Naeger
authors.affiliation: Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Harrington
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D000077562:Valganciclovir; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D050505:Mutant Proteins; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D000077562:Valganciclovir; D015774:Ganciclovir
keywords: Cidofovir; Cytomegalovirus; Foscarnet; Ganciclovir; Resistance; Valganciclovir