Cross-reactive CD8 + T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

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Abstract
Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 “Spanish flu” rather than more recent “seasonal” strains. We present immunological and structural analyses of cross-reactive CD8+ T-cell–mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP418–426 peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8+ T-cell specificity was probed for 12 different NP418 mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP418 mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP418 variant or the 1918-NP418 variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8+ T cells specific for the 2009-NP418 and 1918-NP418 epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.