Antigenic Drift in the Influenza A Virus (H3N2) Nucleoprotein and Escape from Recognition by Cytotoxic T Lymphocytes

Abstract

Viruses exploit different strategies to escape immune surveillance, including the introduction of mutations in cytotoxic T-lymphocyte (CTL) epitopes. The sequence of these epitopes is critical for their binding to major histocompatibility complex (MHC) class I molecules and recognition by specific CTLs, both of which interactions may be lost by mutation. Sequence analysis of the nucleoprotein gene of influenza A viruses (H3N2) isolated in The Netherlands from 1989 to 1999 revealed two independent amino acid mutations at the anchor residue of the HLA-B27-specific CTL epitope SRYWAIRTR (383 to 391). A R384K mutation was found in influenza A viruses isolated during the influenza season 1989–1990 but not in subsequent seasons. In the influenza season 1993–1994, a novel mutation in the same CTL epitope at the same position was introduced. This R384G mutation proved to be conserved in all influenza A viruses isolated from 1993 onwards. Both mutations R384K and R384G abrogated MHC class I presentation and allowed escape from recognition by specific CTLs.

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.…”

HLA class I molecules consistently present internal influenza epitopes

“…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.…”

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).…”

“…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). The R384G mutation resulted in the loss of the anchor residue and as a result ablated recognition by CTLs (15,17). The loss of this epitope affected the human in vitro CTL response significantly (1).…”