West Nile virus–associated HLA-DRB1 alleles in the Greek population: A structural perspective

The HLA system plays a significant role via the regulation of the immune system and contributes to the progression and protection of many diseases. In our previous study, several HLA-DRB1 alleles were found to have a susceptible or protective role toward infection and neuroinvasion of West Nile Virus (WNV) in the Greek population. As expected, the majority of polymorphic positions are located in the peptide-binding region of the molecule. In the present work, the structure of these alleles was studied in silico, to examine the effect of polymorphism on the conformation of DRB1 proteins, with the aspect of WNV association. More specifically, molecular dynamics simulations were used for structural prediction of 23 available alleles. These modeled alleles were evaluated using root-mean-square deviation (RMSD) and root-mean-square fluctuation analysis. Low RMSD values indicate that different alleles have similar structures. Furthermore, low fluctuation was observed in the peptide-binding region between alleles with the higher and the lowest RMSD values. These findings indicate that probably variable residues do not affect the behavior of DRB1 alleles in WNV disease, by causing structural differences between them. © 2022 The Authors. Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd

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 (HLADQA1) significantly influenced the peptide binding while DYWLR/EFA combination (HLADRB1) 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. © 2018 Sarri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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 (HLADQA1) significantly influenced the peptide binding while DYWLR/EFA combination (HLADRB1) 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. © 2018 Sarri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited