title: Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants.
abstract: Amino acid substitutions have been identified in the influenza A virus nucleoprotein that are associated with escape from recognition by virus-specific cytotoxic T lymphocytes (CTLs). One of these is the arginine-to-glycine substitution at position 384 (R384G). This substitution alone, however, is detrimental to viral fitness, which is overcome in part by the functionally compensating co-mutation E375G. Here, the effect on viral fitness of four other co-mutations associated with R384G was investigated by using plasmid-driven rescue of mutant viruses. Whilst none of these alternative co-mutations alone compensated functionally for the detrimental effect of the R384G substitution, the M239V substitution improved viral fitness of viruses containing 375G and 384R. The nucleoprotein displays unexpected flexibility to overcome functional constraints imposed by CTL epitope sequences, allowing influenza viruses to escape from specific CTLs.
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: G F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: E G M
authors.initials: EGM
authors.lastname: Berkhoff
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: N J
authors.initials: NJ
authors.lastname: Nieuwkoop
authors.affiliation: Department of Zoology, Cambridge University, Cambridge, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: R A M
authors.initials: RAM
authors.lastname: Fouchier
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: A D M E
authors.initials: ADME
authors.lastname: Osterhaus
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D000939:Epitopes / Q000235:genetics; D005816:Genetic Complementation Test; D005998:Glycine / Q000235:genetics; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009154:Mutation; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014758:Viral Core Proteins / Q000235:genetics*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000939:Epitopes; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D001120:Arginine; D005998:Glycine