NATURALLY PROCESSED PEPTIDES FROM 2 DISEASE-RESISTANCE-ASSOCIATED HLA-DR13 ALLELES SHOW RELATED SEQUENCE MOTIFS AND THE EFFECTS OF THE DIMORPHISM AT POSITION-86 OF THE HLA-DR-BETA CHAIN

HLA-DR13 has been associated with resistance to two major infectious d iseases of humans, To investigate the peptide binding specificity of t wo HLA-DR13 molecules and the effects of the Gly/Val dimorphism at pos ition 86 of the HLA-DR beta chain on natural peptide ligands, these pe ptides were acid-eluted from immunoaffinity-purified HLA-DRB11301 and -DRB11302, molecules that differ only at this position, The eluted p eptides were subjected to pool sequencing or individual peptide sequen cing by tandem MS or Edman microsequencing, Sequences were obtained fo r 23 peptides from nine source proteins, Three pool sequences for each allele and the sequences of individual peptides were used to define b inding motifs for each allele, Binding specificities varied only at th e primary hydrophobic anchor residue, the differences being a preferen ce for the aromatic amino acids Tyr and Phe in DRB11302 and a prefere nce for Val in DRB11301, Synthetic analogues of the eluted peptides s howed allele specificity in their binding to purified HLA-DR, and Ala- substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1:':1302 (th ose that use aromatic amino acids as primary anchors) to bind to DRB1 1301 confirmed the different preferences for peptide anchor residues c onferred by the Gly --> Val change at position 86, These data suggest a molecular basis for the differential associations of HLA-DRB11301 a nd DRB11302 with resistance to severe malaria and clearance of hepati tis B virus infection.