title: Comparative Analysis of the Endogenous Peptidomes Displayed by HLA-B*27 and Mamu-B*08: Two MHC Class I Alleles Associated with Elite Control of HIV/SIV Infection.
abstract: Indian rhesus macaques are arguably the most reliable animal models in AIDS research. In this species the MHC class I allele Mamu-B*08, among others, is associated with elite control of SIV replication. A similar scenario is observed in humans where the expression of HLA-B*27 or HLA-B*57 has been linked to slow or no progression to AIDS after HIV infection. Despite having large differences in their primary structure, it has been reported that HLA-B*27 and Mamu-B*08 display peptides with sequence similarity. To fine-map the Mamu-B*08 binding motif and assess its similarities with that of HLA-B*27, we affinity purified the peptidomes bound to these MHC class I molecules and analyzed them by LC-MS, identifying several thousands of endogenous ligands. Sequence analysis of both sets of peptides revealed a degree of similarity in their binding motifs, especially at peptide position 2 (P2), where arginine was present in the vast majority of ligands of both allotypes. In addition, several differences emerged from this analysis: (i) ligands displayed by Mamu-B*08 tended to be shorter and to have lower molecular weight, (ii) Mamu-B*08 showed a higher preference for glutamine at P2 as a suboptimal binding motif, and (iii) the second major anchor position, found at PΩ, was much more restrictive in Mamu-B*08. In this regard, HLA-B*27 bound efficiently peptides with aliphatic, aromatic (including tyrosine), and basic C-terminal residues while Mamu-B*08 preferred peptides with leucine and phenylalanine in this position. Finally, in silico estimations of binding efficiency and competitive binding assays to Mamu-B*08 of several selected peptides revealed a good correlation between the characterized anchor motif and binding affinity. These results deepen our understanding of the molecular basis of the presentation of peptides by Mamu-B*08 and can contribute to the detection of novel SIV epitopes restricted by this allotype.
authors.affiliation: Proteomics Unit, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Marcilla
authors.affiliation: Immunology Unit, Department of Cell Biology, Physiology and Immunology and Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona , 08193 Bellaterra, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Alvarez
authors.affiliation: Proteobotics SL, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Fernández
authors.affiliation: Proteomics Unit, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Lombardía
authors.affiliation: Proteomics Unit, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Paradela
authors.affiliation: Proteomics Unit, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Albar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D060467:Disease Resistance; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D008253:Macaca mulatta; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D020543:Proteome / Q000737:chemistry / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*
chemical_list: D015235:HLA-B Antigens; C103707:HLA-B57 antigen; D010446:Peptide Fragments; D020543:Proteome
keywords: HIV; HLA-B*27; MHC; Mamu-B*08; SIV; binding motif; mass spectrometry; peptides; peptidomics