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Influence of genome-scale RNA structure disruption on the replication of murine norovirus--similar replication kinetics in cell culture but attenuation of viral fitness in vivo
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McFadden, Nora, Arias, Armando, Dry, Inga, Bailey, Dalan, Witteveldt, Jeroen, Evans, David J., Goodfellow, Ian and Simmonds, Peter (2013) Influence of genome-scale RNA structure disruption on the replication of murine norovirus--similar replication kinetics in cell culture but attenuation of viral fitness in vivo. Nucleic Acids Research, Volume 41 (Number 12). pp. 6316-6331. doi:10.1093/nar/gkt334 ISSN 0305-1048.
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WRAP_Evans_Nucl. Acids Res.-2013-McFadden-6316-31.pdf - Published Version Available under License Creative Commons Attribution. Download (1030Kb) | Preview |
Official URL: http://dx.doi.org/10.1093/nar/gkt334
Abstract
Mechanisms by which certain RNA viruses, such as hepatitis C virus, establish persistent infections and cause chronic disease are of fundamental importance in viral pathogenesis. Mammalian positive-stranded RNA viruses establishing persistence typically possess genome-scale ordered RNA secondary structure (GORS) in their genomes. Murine norovirus (MNV) persists in immunocompetent mice and provides an experimental model to functionally characterize GORS. Substitution mutants were constructed with coding sequences in NS3/4- and NS6/7-coding regions replaced with sequences with identical coding and (di-)nucleotide composition but disrupted RNA secondary structure (F1, F2, F1/F2 mutants). Mutants replicated with similar kinetics to wild-type (WT) MNV3 in RAW264.7 cells and primary macrophages, exhibited similar (highly restricted) induction and susceptibility to interferon-coupled cellular responses and equal replication fitness by serial passaging of co-cultures. In vivo, both WT and F1/F2 mutant viruses persistently infected mice, although F1, F2 and F1/F2 mutant viruses were rapidly eliminated 1–7 days post-inoculation in competition experiments with WT. F1/F2 mutants recovered from tissues at 9 months showed higher synonymous substitution rates than WT and nucleotide substitutions that potentially restored of RNA secondary structure. GORS plays no role in basic replication of MNV but potentially contributes to viral fitness and persistence in vivo.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics Q Science > QR Microbiology > QR355 Virology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Library of Congress Subject Headings (LCSH): | RNA viruses, Viruses , Virus diseases , Viral genetics, Microbial genetics, Virology, Molecular microbiology , Molecular virology | ||||
Journal or Publication Title: | Nucleic Acids Research | ||||
Publisher: | Oxford University Press | ||||
ISSN: | 0305-1048 | ||||
Official Date: | July 2013 | ||||
Dates: |
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Volume: | Volume 41 | ||||
Number: | Number 12 | ||||
Page Range: | pp. 6316-6331 | ||||
DOI: | 10.1093/nar/gkt334 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 24 December 2015 | ||||
Date of first compliant Open Access: | 24 December 2015 | ||||
Funder: | Wellcome Trust (London, England), University of Edinburgh | ||||
Grant number: | WT087628MA; WT097997MA (WT) ; |
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