title: 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 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.
authors: Department of Pathology, 3.206B Mary Moody Northen Pavilion, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0436, USA.
authors: Shannan L
authors: SL
authors: Rossi
authors: Rafik
authors: R
authors: Fayzulin
authors: Nathan
authors: N
authors: Dewsbury
authors: Nigel
authors: N
authors: Bourne
authors: Peter W
authors: PW
authors: Mason
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D005260:Female; D016679:Genome, Viral; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000096:biosynthesis; D051379:Mice; D009154:Mutation; D012093:Replicon; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*; D014902:West Nile virus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*
chemical_list: D017361:Viral Nonstructural Proteins; D007372:Interferons