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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

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Nucl._Acids_Res._2014_Atkinson_4527_45.pdf (13.80Mb)
Date
07/04/2014
Author
Atkinson, Nicky J.
Witteveldt, Jeroen
Evans, David J.
Simmonds, Peter
Keywords
Hepatitis-C-virus
Protein-synthesis
Codon usage
Coxsackievirus replication
Mutational robustness
QA75 Electronic computers. Computer science
Metadata
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Abstract
Most 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.
Citation
Atkinson , 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/gku075
Publication
Nucleic Acids Research
Status
Peer reviewed
DOI
https://doi.org/10.1093/nar/gku075
ISSN
0305-1048
Type
Journal article
Rights
© The Author(s) 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Description
Wellcome Trust [WT087628MA]; Programme Grant from the MRC [G0401584]. Funding for open access charge: University of Edinburgh. Date of Acceptance: 02/01/2014
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/7341

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