Role of polymorphic residues of human leucocyte antigen-DR molecules on the binding of human immunodeficiency virus peptides.
A study was made of the binding properties of 96 human immunodeficiency virus peptides to human leucocyte antigen (HLA)-DR1 and HLA-DR103 molecules, which differ by three amino acids at positions 67, 70 and 71 in the beta chains. The affinity of the peptides was characterized by their inhibitory concentrations in competitive binding assays which displace half of the labelled influenza haemagglutinin peptide HA306-318 (IC50). Among the high-affinity peptides (IC50 < or = 1 microM), seven bound to DR1, three to DR103 and five equally well to both alleles (promiscuous peptides). Thirty-two other peptides showed medium or low affinity for DR molecules. The role of polymorphic residues was analysed using six mutated DR molecules, intermediates between DR1 and DR103 and differing by one or two substitutions at positions 67, 70 or 71. We reached the same conclusions when using DR1-specific or DR103-specific peptides: modification of residue 70 had no effect on peptide affinity, but single substitution at positions 67 or 71 decreased the allele specificity of the peptides while double substitution at 67 and 71 completely reversed the peptide specificity. In functional assays, DR-binding peptides are able to outcompete specific T-cell proliferation. Furthermore, modification at position 67 or 70 significantly affects the T-cell response and mutation at position 71 abolishes completely the T-cell proliferation. Thus, the polymorphic positions 67 and 71 contributed to the peptide binding with direct effects on T-cell receptor (TCR) recognition while position 70 seems to be mostly engaged in TCR interactions. Furthermore, our results suggest that polymorphic residues may select allele-specific peptides and also influence the conformation of promiscuous peptides.
Jurcevic
S
S
INSERM Unité 395, Université Paul Sabatier, Toulouse, France.
Praud
C
C
Coppin
H L
HL
Bertrand
A
A
Ricard
S
S
Thomsen
M
M
Lakhdar-Ghazal
F
F
De Preval
C
C
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001667:Binding, Competitive; D002455:Cell Division; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006678:HIV; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015798:HLA-DR1 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015693:Gene Products, nef; D015699:HIV Envelope Protein gp120; C059827:HIV gag protein p25; D015798:HLA-DR1 Antigen; C100845:HLA-DR103 antigen; D011948:Receptors, Antigen, T-Cell; D012191:Retroviridae Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C061169:p18 gag protein, Human immunodeficiency virus 1