biostudies-literatureValkenburg SANIAID NIH HHS5570-5https://www.ebi.ac.uk/biostudies/studies/S-EPMC3619348biostudies-literatureUnknown110(14)A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial "hole" in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serolProceedings of the National Academy of Sciences of the United States of AmericaPreemptive priming readily overcomes structure-based mechanisms of virus escape.PMC3619348AI170251Purcell AWDoherty PCBird NARossjohn JGras SJackson DCTurner SJValkenburg SATwist KAHalim HGuillonneau CHatton LAKedzierska KfalsePreemptive priming readily overcomes structure-based mechanisms of virus escape.A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial "hole" in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serol2013-01-01T00:00:00Z2013 Apr2026-05-01T20:55:37.208Z2026-04-07T17:14:57.248ZS-EPMC36193482349355810.1073/pnas.1302935110