Role of polymorphic residues of human leucocyte antigen‐DR molecules on the binding of human immunodeficiency virus peptides

Abstract

SUMMARYA 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 b 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 ). Among the high-affinity peptides (IC 50 4 1 m M), 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.

Association of the HLA-DRB1 epitope LA67, 74 with rheumatoid arthritis and citrullinated vimentin binding

“…Similarly, Fu et al (25) demonstrated that an A 74 →E 74 substitution inhibited T cell responses to hemagglutinin peptide 307–319 without inhibiting peptide binding. In contrast, Jurcevic et al (26) demonstrated that positions 67 and 71 contributed equally and synergistically to human immunodeficiency virus peptide binding to DRB1*01:03. More recently, Menconi et al (27) reported that DRB1 residues 67 and 74 are strongly associated with the development of autoimmune polyglandular syndrome.…”

T cell responses to a mixture of Mycobacterium tuberculosis peptides with complementary HLA-DR binding profiles

“…Purification of HLA-DR molecules HLA-DR molecules were purified essentially as described before [14,15]. Briefly, Epstein-Barr virus (EBV)-transformed HLA-DR homozygous lymphoblastoid B cell lines (LBL), HOM-2, MGAR, VAVY, BOLETH, SWEIG, AMALA, MOU, MADURA and DKB, were lysed at 10 8 cells/ml in PBS containing 1% NP-40, 0 .…”

Targeting strategies for delivery of anti-HIV drugs

“…The HIV peptides show high affinity to the HLA-DR moieties. A study has also demonstrated the high affinity of certain HIV-derived peptides to the HLA-DR on the cell surface [48]. Studies indicate that the HLA-DR is incorporated into the viral envelope at the budding stage of the HIV cycle and facilitates further infection of the other uninfected cells using the CD4 receptor as the receptor.…”