title: Redundancy of the influenza A virus-specific cytotoxic T lymphocyte response in HLA-B*2705 transgenic mice limits the impact of a mutation in the immunodominant NP(383-391) epitope on influenza pathogenesis.
abstract: During the 1993-1994 flu season, influenza A/H3N2 viruses emerged with an amino acid substitution (R384G) at the anchor residue of the HLA-B*2705 restricted NP(383-391) epitope located in the nucleoprotein (NP). The R384G substitution reached fixation rapidly and abrogated recognition of A/H3N2 viruses by NP(383-391)-specific CD8+ T cytotoxic T lymphocytes (CTL) completely. To test the impact of the R384G substitution in the immunodominant NP(383-391) epitope in vivo, influenza A viruses that differ at position 384 of the NP only were generated by reverse genetics. These viruses with an arginin (384R) or a glycin (384G) at position 384 were used to inoculate HLA-B*2705-transgenic mice and C57Bl/6 mice. Infection of naïve C57Bl/6 and HLA-B*2705 mice with influenza virus containing the NP(383-391) epitope (384R) caused more weight loss compared to infection with the virus without the epitope (384G). In contrast, HLA-B*2705 transgenic mice primed for a secondary CTL response by infection with a heterosubtypic influenza A virus, did not display this difference in virulence and the outcome of infection with the 384R virus was somewhat reduced. This phenotype of the 384R-virus was not observed in primed C57Bl/6 mice lacking HLA-B*2705. The relative reduction of weight loss after infection of primed HLA-B*2705+ mice with the 384R virus correlated with the CTL response to the NP(383-391). However, no differences were observed in the kinetics of viral clearance between the two viruses in immune HLA-B*2705+ mice, which may be attributed at least partially to CTL responses to other HLA-B*2705 restricted epitopes that were similar in magnitude.
authors.affiliation: Department of Virology, Erasmus MC, Dr Molewaterplein 50, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Bodewes
authors.forename: M M
authors.initials: MM
authors.lastname: Geelhoed-Mieras
authors.forename: N J
authors.initials: NJ
authors.lastname: Nieuwkoop
authors.forename: J A
authors.initials: JA
authors.lastname: Hanson
authors.forename: C S
authors.initials: CS
authors.lastname: David
authors.forename: R A M
authors.initials: RA
authors.lastname: Fouchier
authors.forename: A D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: G F
authors.initials: GF
authors.lastname: Rimmelzwaan
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001835:Body Weight; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D016056:Immunodominant Epitopes; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins