Patient-Derived Cytomegaloviruses with Different Ganciclovir Sensitivities from UL97 Mutation Retain Their Replication Efficiency and Some Kinase Activity In Vitro

Diana D Wong; Wendy J van Zuylen; Stuart T Hamilton; Mirjam Steingruber; Eric Sonntag; Manfred Marschall; William D Rawlinson

doi:10.1128/AAC.02425-18

Patient-Derived Cytomegaloviruses with Different Ganciclovir Sensitivities from UL97 Mutation Retain Their Replication Efficiency and Some Kinase Activity In Vitro

Antimicrob Agents Chemother. 2019 Aug 23;63(9):e02425-18. doi: 10.1128/AAC.02425-18. Print 2019 Sep.

Authors

Diana D Wong^{1

2}, Wendy J van Zuylen^{1

2}, Stuart T Hamilton^{1

3}, Mirjam Steingruber⁴, Eric Sonntag⁴, Manfred Marschall⁴, William D Rawlinson^{5

2

3

6}

Affiliations

¹ Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, Australia.
² School of Medical Sciences, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, Australia.
³ School of Women's and Children's Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, Australia.
⁴ Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
⁵ Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, Australia w.rawlinson@unsw.edu.au.
⁶ School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales Sydney, NSW, Australia.

Abstract

Mutations in the cytomegalovirus UL97 kinase gene contribute to antiviral resistance. Mutations A594S and G598D from two clinical isolates were analyzed, and bacterial artificial chromosome (BAC)-engineered A594S recombinant cytomegalovirus exhibited a ganciclovir-resistant phenotype on plaque reduction. Viral replication was comparable to that of the wild type. Cell-based kinase activity and autophosphorylation of ectopically expressed proteins showed that mutants retained some kinase activity. This study showed that patient-derived cytomegalovirus with different ganciclovir sensitivities retained replication efficiency and exhibited some kinase activity in vitro.

Keywords: UL97; cytomegalovirus; drug resistance; ganciclovir; mutation; phosphorylation; protein kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology*
Cell Line
Cell Line, Tumor
Cytomegalovirus / drug effects*
Cytomegalovirus / enzymology*
Cytomegalovirus / genetics
Drug Resistance, Viral / genetics
Ganciclovir / pharmacology*
Humans
Mutation / genetics
Open Reading Frames / genetics
Phosphorylation
Protein Kinases / genetics
Protein Kinases / metabolism*
Virus Replication / drug effects
Virus Replication / genetics

Substances

Antiviral Agents
Protein Kinases
Ganciclovir