Differential properties of cytomegalovirus pUL97 kinase isoforms affect viral replication and maribavir susceptibility

Rike Webel, Morgan Hakki, Mark N. Prichard, William D. Rawlinson, Manfred Marschall, Sunwen Chou

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The human cytomegalovirus (HCMV)-encoded kinase pUL97 is required for efficient viral replication. Previous studies described two isoforms of pUL97, the full-length isoform (M1) and a smaller isoform likely resulting from translation initiation at codon 74 (M74). Here, we report the detection of a third pUL97 isoform during viral infection resulting from translation initiation at codon 157 (isoform M157). The consistent expression of isoform M157 as a minor component of pUL97 during infection with clinical and laboratory-adapted HCMV strains was suppressed when codon 157 was mutagenized. Viral mutants expressing specific isoforms were generated to compare their growth and drug susceptibility phenotypes, as well as pUL97 intracellular localization patterns and kinase activities. The exclusive expression of isoform M157 resulted in substantially reduced viral growth and resistance to the pUL97 inhibitor maribavir while retaining susceptibility to ganciclovir. Confocal imaging demonstrated reduced nuclear import of amino-terminal deletion isoforms compared to isoform M1. Isoform M157 showed reduced efficiency of various substrate protein interactions and autophosphorylation, whereas Rb phosphorylation was preserved. These results reveal differential properties of pUL97 isoforms that affect viral replication, with implications for the antiviral efficacy of maribavir.

Original languageEnglish (US)
Pages (from-to)4776-4785
Number of pages10
JournalJournal of Virology
Volume88
Issue number9
DOIs
StatePublished - 2014

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Cytomegalovirus
virus replication
codons
Human herpesvirus 5
Protein Isoforms
phosphotransferases (kinases)
Phosphotransferases
translation (genetics)
protein phosphorylation
infection
imports
microbial growth
phosphorylation
image analysis
phenotype
drugs
mutants
Initiator Codon
maribavir
proteins

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Differential properties of cytomegalovirus pUL97 kinase isoforms affect viral replication and maribavir susceptibility. / Webel, Rike; Hakki, Morgan; Prichard, Mark N.; Rawlinson, William D.; Marschall, Manfred; Chou, Sunwen.

In: Journal of Virology, Vol. 88, No. 9, 2014, p. 4776-4785.

Research output: Contribution to journalArticle

Webel, Rike ; Hakki, Morgan ; Prichard, Mark N. ; Rawlinson, William D. ; Marschall, Manfred ; Chou, Sunwen. / Differential properties of cytomegalovirus pUL97 kinase isoforms affect viral replication and maribavir susceptibility. In: Journal of Virology. 2014 ; Vol. 88, No. 9. pp. 4776-4785.
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