Mutations in West Nile virus nonstructural proteins that facilitate replicon persistence in vitro attenuate virus replication in vitro and in vivo

Abstract West Nile virus (WNV) infections in vertebrates are generally acute but persistent infections have been observed. To investigate the ability of WNV to produce persistent infections, we forced subgenomic WNV replicons to replicate within a cell without causing cell death. Detailed analyses o...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2007-07, Vol.364 (1), p.184-195
Main Authors: Rossi, Shannan L, Fayzulin, Rafik, Dewsbury, Nathan, Bourne, Nigel, Mason, Peter W
Format: Article
Language:English
Subjects:
Adaptation, Physiological
animal disease models
Animals
Attenuation
Cell Line
Cricetinae
cultured cells
Cytopathogenic Effect, Viral - genetics
Female
Flavivirus
genome
Genome, Viral
HeLa Cells
Humans
Infectious Disease
Innate immune response
Interferon
Interferons - biosynthesis
Mice
Mutation
Nonstructural gene
nonstructural protein
Persistence
point mutation
Replication
Replicon
Viral Nonstructural Proteins - genetics
viral proteins
viremia
virus replication
Virus Replication - genetics
West Nile virus
West Nile virus - genetics
West Nile virus - pathogenicity
West Nile virus - physiology
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Summary:Abstract West Nile virus (WNV) infections in vertebrates are generally acute but persistent infections have been observed. To investigate the ability of WNV to produce persistent infections, we forced subgenomic WNV replicons to replicate within a cell without causing cell death. Detailed analyses of these cell-adapted genomes revealed mutations within the nonstructural protein genes NS2A (D73H, M108K), NS3 (117Kins), NS4B (E249G) and NS5 (P528H). WNV replicons and WNVs harboring a subset of NS2A or NS3 mutations showed a reduction in genome replication, a reduction in antigen accumulation, a decrease in cytopathic effect, an increased ability to persist in cell culture and/or attenuation in vivo . Taken together, these data indicate that WNV with a defect in replication and an increased potential to persist within the host cell can be generated by point mutations at multiple independent loci, suggesting that persistent viruses could arise in nature.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2007.02.009