Show simple item record

Files in this item

Thumbnail

Item metadata

dc.contributor.authorAtkinson, Nicky J.
dc.contributor.authorWitteveldt, Jeroen
dc.contributor.authorEvans, David J.
dc.contributor.authorSimmonds, Peter
dc.date.accessioned2015-08-27T14:40:07Z
dc.date.available2015-08-27T14:40:07Z
dc.date.issued2014-04-07
dc.identifier211241567
dc.identifier92eb8c8d-bc15-4ac8-930c-2e04f903596a
dc.identifier000334761100042
dc.identifier84898943386
dc.identifier.citationAtkinson , N J , Witteveldt , J , Evans , D J & Simmonds , P 2014 , ' The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication ' , Nucleic Acids Research , vol. 42 , no. 7 , pp. 4527-4545 . https://doi.org/10.1093/nar/gku075en
dc.identifier.issn0305-1048
dc.identifier.otherORCID: /0000-0002-1315-4258/work/104252506
dc.identifier.urihttps://hdl.handle.net/10023/7341
dc.descriptionWellcome Trust [WT087628MA]; Programme Grant from the MRC [G0401584]. Funding for open access charge: University of Edinburgh. Date of Acceptance: 02/01/2014en
dc.description.abstractMost RNA viruses infecting mammals and other vertebrates show profound suppression of CpG and UpA dinucleotide frequencies. To investigate this functionally, mutants of the picornavirus, echovirus 7 (E7), were constructed with altered CpG and UpA compositions in two 1.1-1.3 Kbase regions. Those with increased frequencies of CpG and UpA showed impaired replication kinetics and higher RNA/infectivity ratios compared with wild-type virus. Remarkably, mutants with CpGs and UpAs removed showed enhanced replication, larger plaques and rapidly outcompeted wild-type virus on co-infections. Luciferase-expressing E7 sub-genomic replicons with CpGs and UpAs removed from the reporter gene showed 100-fold greater luminescence. E7 and mutants were equivalently sensitive to exogenously added interferon-beta, showed no evidence for differential recognition by ADAR1 or pattern recognition receptors RIG-I, MDA5 or PKR. However, kinase inhibitors roscovitine and C16 partially or entirely reversed the attenuated phenotype of high CpG and UpA mutants, potentially through inhibition of currently uncharacterized pattern recognition receptors that respond to RNA composition. Generating viruses with enhanced replication kinetics has applications in vaccine production and reporter gene construction. More fundamentally, the findings introduce a new evolutionary paradigm where dinucleotide composition of viral genomes is subjected to selection pressures independently of coding capacity and profoundly influences host-pathogen interactions.
dc.format.extent19
dc.format.extent14474862
dc.language.isoeng
dc.relation.ispartofNucleic Acids Researchen
dc.subjectHepatitis-C-virusen
dc.subjectProtein-synthesisen
dc.subjectCodon usageen
dc.subjectCoxsackievirus replicationen
dc.subjectMutational robustnessen
dc.subjectQA75 Electronic computers. Computer scienceen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccQA75en
dc.titleThe influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replicationen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.identifier.doi10.1093/nar/gku075
dc.description.statusPeer revieweden


This item appears in the following Collection(s)

Show simple item record