pr5b01146_si_006.pdf (132.5 kB)
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
journal contribution
posted on 2016-01-26, 00:00 authored by Miguel Marcilla, Iñaki Alvarez, Antonio Ramos-Fernández, Manuel Lombardía, Alberto Paradela, Juan Pablo AlbarIndian
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.