Mutational analysis of the West Nile virus NS4B protein

Details

• Alternative Title:
  Virology
• Personal Author:
  Wicker, Jason A. ; Whiteman, Melissa C. ; Beasley, David W.C. ; Davis, C. Todd ; McGee, Charles E. ; Lee, J. Ching ; Higgs, Stephen ; Kinney, Richard M. ; Huang, Claire Y.-H. ; Barrett, Alan D.T.
• Description:
  West Nile virus NS4B is a small hydrophobic nonstructural protein approximately 27 kDa in size whose function is poorly understood. Amino acid substitutions were introduced into the NS4B protein primarily targeting two distinct regions; the N-terminal domain (residues 35 through 60) and the central hydrophobic domain (residues 95 through 120). Only the NS4B P38G substitution was associated with both temperature-sensitive and small-plaque phenotypes. Importantly, this mutation was found to attenuate neuroinvasiveness greater than 10,000,000-fold and lower viremia titers compared to the wild-type NY99 virus in a mouse model. Full genome sequencing of the NS4B P38G mutant virus revealed two unexpected mutations at NS4B T116I and NS3 N480H (P38G/T116I/N480H), however, neither mutation alone was temperature sensitive or attenuated in mice. Following incubation of P38G/T116I/N480H at 41°C, five mutants encoding compensatory substitutions in the NS4B protein exhibited a reduction in the temperature-sensitive phenotype and reversion to a virulent phenotype in the mouse model.
• Subjects:
  Amino Acid Sequence Amino Acid Substitution Animals Article Attenuated Phenotype DNA Mutational Analysis Female Flavivirus Humans Mice Molecular Sequence Data Mutation, Missense NS4B Protein Sequence Alignment Temperature Sensitivity Viral Nonstructural Proteins Virulence West Nile Virus

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• Source:
  Virology. 426(1):22-33
• Pubmed ID:
  22314017
• Pubmed Central ID:
  PMC4583194
• Document Type:
  Journal Article
• Funding:
  CC999999/ImCDC/Intramural CDC HHSUnited States/ ; T32 AI007526/AI/NIAID NIH HHSUnited States/ ; T32AI 7526/AI/NIAID NIH HHSUnited States/
• Volume:
  426
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:8941dc2d86f98f78f961e5d3db71ebea091942ad7e6266203873871d3dcbc735
• Download URL:
  https://stacks.cdc.gov/view/cdc/34514/cdc_34514_DS1.pdf
• File Type:
  [PDF - 4.71 MB ]