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J Proteome Res. 2016 Mar 4;15(3):1059-69. doi: 10.1021/acs.jproteome.5b01146. Epub 2016 Feb 8.

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.

Author information

1
Proteomics Unit, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.
2
Immunology Unit, Department of Cell Biology, Physiology and Immunology and Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona , 08193 Bellaterra, Spain.
3
Proteobotics SL, Spanish National Biotechnology Centre (CSIC), Darwin 3, 28049 Madrid, Spain.

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.

KEYWORDS:

HIV; HLA-B*27; MHC; Mamu-B*08; SIV; binding motif; mass spectrometry; peptides; peptidomics

PMID:
26811146
DOI:
10.1021/acs.jproteome.5b01146
[Indexed for MEDLINE]

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