Simultaneous prediction of binding capacity for multiple molecules of the HLA B44 supertype.
We selected for study a set of B44-supertype molecules collectively represented in >40% of the individuals in all major ethnicities (B*1801, B*4001, B*4002, B*4402, B*4403, and B*4501). The peptide-binding specificity of each molecule was characterized using single amino acid substitution analogues and nonredundant peptide libraries. In all cases, only peptide ligands with glutamic acid in position 2 were preferred. At the C terminus, each allele was associated with a unique but broad pattern of preferences, but all molecules tolerated hydrophobic/aliphatic (leucine, isoleucine, valine, methionine), aromatic (tyrosine, phenylalanine, tryptophan), and small (alanine, glycine, threonine) residues. Secondary anchor motifs were also defined for all molecules. Together, these features were used to define a B44 supermotif and a novel algorithm for calculating degeneracy scores that can be used to predict B44-supertype degenerate binders. Approximately 90% of the peptides with a B44 supermotif degeneracy score of >10 bound at least three of the six B44-supertype molecules studied with high affinity. Finally, a number of peptides derived from hepatitis B and C viruses, HIV, and Plasmodium falciparum have been identified that have degenerate B44 supertype-binding capacity. Taken together, these findings have important implications for epitope-based approaches to vaccination, immunotherapy, and the monitoring of immune responses.
Sidney
John
J
Division of Translational Immunology and Biodefense, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Southwood
Scott
S
Pasquetto
Valerie
V
Sette
Alessandro
A
D000465:Algorithms; D000483:Alleles; D020816:Amino Acid Motifs / Q000276:immunology; D019943:Amino Acid Substitution / Q000276:immunology; D002461:Cell Line, Transformed; D019295:Computational Biology / Q000379:methods; D003429:Cross Reactions; D005787:Gene Frequency; D018698:Glutamic Acid / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D059948:HLA-B44 Antigen; D006650:Histocompatibility Testing / Q000379:methods*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009842:Oligopeptides / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000276:immunology; D012680:Sensitivity and Specificity
D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D018698:Glutamic Acid