Abstract
IntroductionClass I HLA's polymorphism has hampered CTL epitope mapping with laborious experiments. Objectives are 1) to evaluate the novel in silico model in predicting previously reported epitopes in comparison with existing program, and 2) to apply the model to predict optimal epitopes with HLA using experimental results.Materials and MethodsWe have developed a novel in silico epitope prediction method, based on HLA crystal structure and a peptide docking simulation model, calculating the peptide-HLA binding affinity at four amino acid residues in each terminal. It was applied to predict 52 HIV best–defined CTL epitopes from 15-mer overlapping peptides, and its predictive ability was compared with the HLA binding motif-based program of HLArestrictor. It was then used to predict HIV-1 Gag optimal epitopes from previous ELISpot results.Results43/52 (82.7%) epitopes were detected by the novel model, whereas 37 (71.2%) by HLArestrictor. We also found a significant reduction in epitope detection rates for longer epitopes in HLArestrictor (p = 0.027), but not in the novel model. Improved epitope prediction was also found by introducing both models, especially in specificity (p<0.001). Eight peptides were predicted as novel, immunodominant epitopes in both models.DiscussionThis novel model can predict optimal CTL epitopes, which were not detected by an existing program. This model is potentially useful not only for narrowing down optimal epitopes, but predicting rare HLA alleles with less information. By introducing different principal models, epitope prediction will be more precise.
Highlights
Class I Human Leukocyte Antigen (HLA)’s polymorphism has hampered Cytotoxic T lymphocytes (CTLs) epitope mapping with laborious experiments
We have evaluated the predictive power of our docking simulation model (DSM) by testing its ability to predict epitopes within 52 15-mer peptides spanning the epitopes for seven HLA alleles enlisted in the Los Alamos database as best-defined epitopes
This was comparable to the HLArestrictor, where 37/52 (71.2%, 43/ 52 vs 37/52, p = 0.24 by Fisher’s exact test) best-defined epitopes scored within the threshold of binding affinity without having 4 or more other candidate epitopes: 20 as Strong Binder (SB), 10 as Weak Binder (WB) and 7 as Combined Binder (CB)
Summary
Class I HLA’s polymorphism has hampered CTL epitope mapping with laborious experiments. Cytotoxic T lymphocytes (CTLs) play a crucial role in HIV replication control by eliminating virus-infected cells by recognizing class I Human Leukocyte Antigen (HLA) molecule-viral peptides ( = epitope) complex This response is thought to be a major determinant of the viral set point, and consequent disease progression [1]. The extensive diversity of HIV-1 owing to its extreme capacity to mutate has led to a reported 13 prototype clades and 43 circulating recombinant forms (CRFs) [4] Despite such HLA polymorphism and HIV viral diversity environment, recent genome wide association study (GWAS) reported the best contribution of class I HLA for viral control, suggesting the importance of CTL epitope mapping with responsible HLA information [5]. The limitation of the dataset currently available is that the majority of these epitope/HLA combinations are derived from subtype Binfected Caucasians or C-infected Africans, and epitope information from other subtypes or ethnicities is rare
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