Amino acid signatures in the HLA class II peptide-binding region associated with protection/susceptibility to the severe West Nile Virus disease

The MHC class II region in humans is highly polymorphic. Each MHC molecule is formed by an α and a β chain, produced by different genes, creating an antigen-binding groove. In the groove there are several pockets into which antigens anchor and fit. The affinity of this fitting determines the recognition specificity of a given peptide. Here, based on our previous results about the association of MHC class II with the WNV disease, we examined the role of the binding pockets of HLA-DPA1, -DQA1 and–DRB1 in the severe form of the disease. In HLA-DQA1, variants in all pockets 1, 6 and 9 were found to be associated with either protection and/or susceptibility to neuroinvasion caused by WNV. Similarly, pockets 7, 9 and 10 in HLA-DRB1 were associated with severe disease. Protein modeling of these molecules revealed structural and functional differences among alleles with opposite roles concerning the development of the disease. Different amino acids in positions α52 and α66 (HLA-DQA1) significantly influenced the peptide binding while DYWLR/EFA combination (HLA-DRB1) was associated with neuronal damage. Further studies could help us understand the selectivity of pocket variants in order to create suitable peptides for an effective response.