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: R Bodewes, M M Geelhoed-Mieras, N J Nieuwkoop, J A Hanson, C S David, R A M Fouchier, A D M E Osterhaus, G F Rimmelzwaan
• Journal: Virus research (Virus Res) Vol. 155 Issue 1 Pg. 123-30 (Jan 2011) ISSN: 1872-7492 [Electronic] Netherlands
• PMID: 20863862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• HLA-B*27:05 antigen
• HLA-B27 Antigen
• Immunodominant Epitopes
• NP protein, Influenza A virus
• Nucleocapsid Proteins
• RNA-Binding Proteins
• Viral Core Proteins

Topics

• Amino Acid Substitution (genetics)
• Animals
• Body Weight
• CD8-Positive T-Lymphocytes (immunology)
• Disease Models, Animal
• Female
• HLA-B27 Antigen (genetics, immunology)
• Immunodominant Epitopes (genetics, immunology)
• Influenza A Virus, H3N2 Subtype (genetics, immunology, pathogenicity)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation, Missense
• Nucleocapsid Proteins
• Orthomyxoviridae Infections (immunology, pathology, virology)
• RNA-Binding Proteins (genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Viral Core Proteins (genetics, immunology)