HLArestrictor—a tool for patient-specific predictions of HLA restriction elements and optimal epitopes within peptides

Abstract

Traditionally, T cell epitope discovery requires considerable amounts of tedious, slow, and costly experimental work. During the last decade, prediction tools have emerged as essential tools allowing researchers to select a manageable list of epitope candidates to test from a larger peptide, protein, or even proteome. However, no current tools address the complexity caused by the highly polymorphic nature of the restricting HLA molecules, which effectively individualizes T cell responses. To fill this gap, we here present an easy-to-use prediction tool named HLArestrictor ( http://www.cbs.dtu.dk/services/HLArestrictor ), which is based on the highly versatile and accurate NetMHCpan predictor, which here has been optimized for the identification of both the MHC restriction element and the corresponding minimal epitope of a T cell response in a given individual. As input, it requires high-resolution (i.e., 4-digit) HLA typing of the individual. HLArestrictor then predicts all 8-11mer peptide binders within one or more larger peptides and provides an overview of the predicted HLA restrictions and minimal epitopes. The method was tested on a large dataset of HIV IFNγ ELIspot peptide responses and was shown to identify HLA restrictions and minimal epitopes for about 90% of the positive peptide/patient pairs while rejecting more than 95% of the negative peptide-HLA pairs. Furthermore, for 18 peptide/HLA tetramer validated responses, HLArestrictor in all cases predicted both the HLA restriction element and minimal epitope. Thus, HLArestrictor should be a valuable tool in any T cell epitope discovery process aimed at identifying new epitopes from infectious diseases and other disease models.

A Population Response Analysis Approach To Assign Class II HLA-Epitope Restrictions

“…We also analyzed the peptide-allele restrictions confirmed by Larsen et al (2010) (29). Out of the 18 peptides and respective restricting alleles, 7 peptide-allele combinations were present in RATE results for Los Alamos HIV database data set with the allele being expressed in at least one positive donor.…”

HIV Control through a Single Nucleotide on the HLA-B Locus

“…S1 and Table S1 in the supplemental material), even though this HLA residue is one that is likely to affect both the B and C pockets of the peptidebinding groove (35). The failure of Gag-TL9 to bind adequately to HLA-B*42:02 could not be predicted using in silico-based prediction programs (13,47) or by experimentally determined peptidebinding motifs (25). There is no other example of closely related HLA molecules that differ only by the single Tyr¡His change at HLA residue 9 (38).…”

Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

“…Although PPIPVGDIY (PY9) has appeared in the "A" list of HIV-specific CD8 ϩ T-cell epitopes since 1995 (48) and epitope prediction programs predict that PY9 would bind better than NY10 to HLA-B*3501 (17), nonetheless PY9 is not the epitope. It is significant that 0/377 peptides eluted from HLA class I molecules and sequenced have Pro at P1 (44).…”