Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir

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Abstract

Mutations in the human CMV UL97 kinase gene are a major mechanism of viral resistance to two anti-CMV drugs, ganciclovir (GCV) and maribavir (MBV). GCV, the most widely used and established therapy for CMV, is a substrate for the UL97 kinase. Well-characterised GCV-resistance mutations at UL97 codons 460, 520 and 590-607 impair the phosphorylation of GCV that is necessary for its antiviral activity, presumably by altering substrate recognition. In contrast, MBV is an inhibitor of the UL97 kinase and is the first new CMV therapy to reach later stage clinical trials in many years. No MBV-resistant CMV isolates have yet been detected in clinical trials, but after culture propagation under drug, UL97 mutations that confer moderate to high-level MBV resistance have been identified at codons 353, 397, 409 and 411. These mutations are located upstream of the GCV-resistance mutations and are close to the ATP-binding and catalytic domains common to all kinases, consistent with MBV acting as a small molecule ATP-competitive kinase inhibitor. So far, no UL97 mutations are known to confer resistance to both GCV and MBV.

Original languageEnglish (US)
Pages (from-to)233-246
Number of pages14
JournalReviews in Medical Virology
Volume18
Issue number4
DOIs
StatePublished - Jul 2008

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Ganciclovir
Cytomegalovirus
Phosphotransferases
Mutation
Codon
Adenosine Triphosphate
Clinical Trials
Pharmaceutical Preparations
Antiviral Agents
maribavir
Catalytic Domain
Phosphorylation
Therapeutics
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir. / Chou, Sunwen.

In: Reviews in Medical Virology, Vol. 18, No. 4, 07.2008, p. 233-246.

Research output: Contribution to journalArticle

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