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 NP383–391 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 NP383–391 epitope located in the nucleoprotein (NP). The R384G substitution reached fixation rapidly and abrogated recognition of A/H3N2 viruses by NP383–391-specific CD8+ T cytotoxic T lymphocytes (CTL) completely. To test the impact of the R384G substitution in the immunodominant NP383–391 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 NP383–391 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 NP383–391. 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.

Research highlights▶ CD8+ T cells play an important role in the control of influenza virus infections. ▶ The effect of a mutation in the HLA-B*2705 restricted NP383 epitope was evaluated in vivo. ▶ Infection with NP384R virus caused more weight loss in control mice but not in primed HLA-B*2705 mice. ▶ This correlated with the redundant CD8+ T cell response observed in these mice. ▶ The redundant CTL response might explain the absence of differences in viral clearance.