Influenza is a highly infectious disease caused by the influenza virus resulting in more than 500,000 deaths worldwide. The influenza virus has a high mutation rate which allows for immune escape, and therefore requires an updated vaccine annually. Despite this high mutation rate, amino acids position 265-273 of the Influenza A virus (IAV) nucleoprotein (NP) are conserved, and contain an immunodominant epitope presented by the Human Leukocyte Antigen (HLA) A*03:01, a HLA within the HLA-A3 super family. In some cases, it has been discovered that HLA molecules within the same superfamily can present the same processed peptides from pathogenic proteins to T cells to eliminate pathogen invasion.
Our work focused on HLA-A*03:01, HLA-A*11:01 and HLA-A*68:01, all members of the HLA-A3 superfamily with polymorphisms at 6 positions within the antigen binding cleft. We hypothesised that all three HLAs will be able to present the NP265-273 peptide, albeit in different ways, which we structurally characterised using X-ray crystallography.
For structural characterisation of the HLA- A*03:01, HLA-A*11:01 and HLA-A*68:01-bound to NP265-273 were produced. The peptide-HLA complexes structures and stability were determined, and show different conformation and stability of the NP265-273 peptide. We show that despite belonging to the same HLA superfamily, buried polymorphism greatly impacted peptide presentation, that in turn was not able to activate T cells in HLA-A*68:01+ or HLA-A*11:01+ individuals.