Sequence Variation in a Newly Identified HLA-B35-Restricted Epitope in the Influenza A Virus Nucleoprotein Associated with Escape from Cytotoxic T Lymphocytes

Abstract

Here, we describe a new HLA-B*3501-restricted cytotoxic T lymphocyte (CTL) epitope in the influenza A virus (H3N2) nucleoprotein, which was found to exhibit a high degree of variation at nonanchor residues. The influenza virus variants emerged in chronological order, and CTLs directed against old variants failed to recognize more recent strains of influenza A virus, indicating an escape from CTL immunity.

HLA class I molecules consistently present internal influenza epitopes

“…Taken together, these data indicate that NP 418 -426 is an epitope that (i) is presented well by the high frequency class I molecule HLA-B*0702 in multiple strains of influenza, (ii) is well recognized by CTL, (iii) is presented by multiple members of the B7 supertype, and (iv) exhibits great diversity in positions 4-8. It therefore appears that members of the B7 supertype have evolved a structure that presents an epitope with a conserved P2 proline anchor and that the influenza virus varies positions 4-8 of this epitope to escape consistent CTL recognition (6).…”

“…It is well documented that antibodies which recognize the HA and NA molecules of one influenza strain may not sufficiently bind to HA and NA molecules of older and/or future strains (2)(3)(4). Viral peptides presented by class I HLA and targeted by CTL likewise exhibit variability through the emergence of viral escape mutants (5,6). Although our knowledge of class I-presented influenza epitopes is incomplete, extensive variability has been reported in some of the viral sequences so far reported as CTL targets (5)(6)(7).…”

“…Viral peptides presented by class I HLA and targeted by CTL likewise exhibit variability through the emergence of viral escape mutants (5,6). Although our knowledge of class I-presented influenza epitopes is incomplete, extensive variability has been reported in some of the viral sequences so far reported as CTL targets (5)(6)(7). Understanding the nature and number of viral epitopes presented following infection would provide important insights to indicate the epitopes that facilitate virus escape and those epitopes upon which the immune response recognizes despite virus variability.…”

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

“…The promiscuity of CD4 and CD8 T cell receptors could allow them to recognize epitopes even after the addition of a point mutation. While escape from CTLs is possible and observable [8][9][10][11], also observable are T cells that recognize a range of peptide sequences . In addition, the functional constraints placed on internal structural genes, inaccessible to antibodies, limit their ability to mutate.…”

Functional Compensation of a Detrimental Amino Acid Substitution in a Cytotoxic-T-Lymphocyte Epitope of Influenza A Viruses by Comutations

“…This escape mechanism has been described predominantly for persistent virus infections. However, epitopes from the influenza virus nucleoprotein (NP) also exhibit amino acid variation associated with escape from recognition by CTLs (2,15,17). The rapid fixation of these mutations was explained by small selective advantages and population dynamics in a theoretical model, using the R384G mutation in the HLA-B*2705-restricted NP 383-391 epitope as an example (4).…”