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.

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.

Bodewes R ，Geelhoed-Mieras MM ，Nieuwkoop NJ ，Hanson JA ，David CS ，Fouchier RA ，Osterhaus AD ，Rimmelzwaan GF ... -  《-》

Influenza virus CTL epitopes, remarkably conserved and remarkably variable.

Rimmelzwaan GF ，Kreijtz JH ，Bodewes R ，Fouchier RA ，Osterhaus AD ... -  《-》

Strong memory CD8+ T cell responses against immunodominant and three new subdominant HLA-B27-restricted influenza A CTL epitopes following secondary infection of HLA-B27 transgenic mice.

Cheuk E ，Chamberlain JW 《CELLULAR IMMUNOLOGY》

Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes.

Rimmelzwaan GF ，Boon AC ，Voeten JT ，Berkhoff EG ，Fouchier RA ，Osterhaus AD ... -  《VIRUS RESEARCH》

A mutation in the HLA-B*2705-restricted NP383-391 epitope affects the human influenza A virus-specific cytotoxic T-lymphocyte response in vitro.

Berkhoff EG ，Boon AC ，Nieuwkoop NJ ，Fouchier RA ，Sintnicolaas K ，Osterhaus AD ，Rimmelzwaan GF ... -  《-》