Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation.
The binding of peptides to MHC class I molecules induces MHC/peptide complexes that have specific conformational features. Little is known about the molecular and structural bases required for an optimal MHC/peptide association able to induce a dominant T cell response. We sought to characterize the interaction between purified HLA-A3 molecules and four well known CD8 epitopes from HIV-1 proteins. To define the characteristics of HLA-peptide complex formation and to identify potential structural changes, we used biochemical assays that detect well formed complexes. We tested the amplitude, stability, and kinetic parameters of the interaction between HLA-A3, peptides, and anti-HLA mAbs. Our results show that the four epitopes Nef73-82, Pol325-333, Env37-46, and Gag20-28 bind strongly to HLA-A3 molecules and form very stable complexes that are detected with differential patterns of mAb reactivity. The most striking result is the nonrecognition of the HLA-A3/Gag20-28 complex by the A11.1M mAb specific to HLA-A3/-A11 alleles. To explain this observation, from the data published on HLA-A11 crystallographic structure, we propose molecular models of the HLA-A3 molecule complexed with Nef73-82, Pol325-333, and Gag20-28 epitopes. In the HLA-A3/Gag20-28 complex, we suggest that Arg at position P1 of the peptide may push the alpha2 helix residue Trp-167 of HLA-A3 and affect mAb recognition. Such observations may have great implications for T cell antigen receptor recognition and the immunogenicity of HLA/peptide complexes.
Racape
Judith
J
Département d'Immunologie, Institut Cochin, F-75014 Paris, France.
Connan
Francine
F
Hoebeke
Johan
J
Choppin
Jeannine
J
Guillet
Jean-Gérard
JG
D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D015791:HLA-A3 Antigen / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D020349:Surface Plasmon Resonance
D000939:Epitopes; D015791:HLA-A3 Antigen; D010446:Peptide Fragments; D001120:Arginine