Abstract
Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide-binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R2 (coefficient of determination), Q2 (cross-validated R2), and RPRE2 (R2 of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non-polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored.
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Park B K, Pirmohamed M, Kitteringham N R. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol, 1998, 11: 969–988
Naisbitt D J, Gordon S, Pirmohamed M, et al. Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment. Drug Saf, 2000, 23: 483–507
Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis, 2006, 43: 99–102
Hetherington S, Hughes A R, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet, 2002, 359: 1121–1122
Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet, 2002, 359: 727–732
Symonds W, Cutrell A, Edwards M, et al. Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther, 2002, 24: 565–573
Chessman D, Lethborg T, Kostenko L, et al. Abacavir hypersensitivity in HLA-B57-positive individuals with HIV infection is dependent upon the conventional MHC-I Ag presentation pathway. Tissue Antigens, 2007, 69: 373–373
Martin A M, Nolan D, Gaudieri S, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B* 5701 and a haplotypic Hsp70-Hom variant. Pnas, 2004, 101: 4180–4185
Gerber B O, Pichler W J. Noncovalent interactions of drugs with immune receptors may mediate drug-induced hypersensitivity reactions. AAPS J, 2006, 8: 160–165
Posadas S, Pichler W. Delayed drug hypersensitivity reactions-new concepts. Clin Exp Allergy, 2007, 37: 989–999
Rozieres A, Vocanson M, Saïd B B, et al. Role of T cells in nonimmediate allergic drug reactions. Curr Opin Allergy Cl, 2009, 9: 305–310
Chung W H, Hung S I, Chen Y T. Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Cl, 2007, 7: 317–323
Adam J, Eriksson K K, Schnyder B, et al. Avidity determines T-cell reactivity in abacavir hypersensitivity. Eur J Immunol, 2012, 1–11
Chessman D, Kostenko L, Lethborg T, et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity, 2008, 28: 822–832
Bharadwaj M, Illing P, Kostenko L. Personalized medicine for HLA-associated drug-hypersensitivity reactions. Pers Med, 2010, 7: 495–516
Trybula W J. Data mining and knowledge discovery. Annu Rev Inform Sci, 1997, 32: 197–229
Vita R, Zarebski L, Greenbaum J A, et al. The immune epitope database 2. 0. Nucleic Acids Res, 2010, 38: D854–D862
Sathiamurthy M, Peters B, Bui H H, et al. An ontology for immune epitopes: application to the design of a broad scope database of immune reactivities. Immunome Res, 2005, 1: 1–10
Mei H, Liao Z H, Zhou Y, et al. A new set of amino acid descriptors and its application in peptide QSARs. Biopolymers, 2005, 80: 775–786
Sanchez A, David V. Advanced support vector machines and kernel methods. Neurocomputing, 2003, 55: 5–20
Schölkopf B, Smola A J. Learning with Kernels: Support Vector Machines, Regularization, Optimization, and Beyond. Boston: The Mit Press, 2001
Tian F, Yang L, Lv F, et al. In silico quantitative prediction of peptides binding affinity to human MHC molecule: an intuitive quantitative structure—activity relationship approach. Amino Acids, 2009, 36: 535–554
Li Z L, Li G R, Shu M, et al. A novel vector of topological and structural information for amino acids and its QSAR applications for peptides and analogues. Sci China Ser B-Chem, 2008, 51: 946–957
Mei H, Zhou Y, Liao Z H, et al. Study on quantitative structure-activity relationships of HLA-A* 0201 restrictive CTL epitopes. Acta Chim Sin, 2006, 64: 949–952
Guan P, Doytchinova I A, Walshe V A, et al. Analysis of peptide-protein binding using amino acid descriptors: prediction and experimental verification for human histocompatibility complex HLA-A*0201. J Med Chem, 2005, 48: 7418–7425
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Zhang, Y., Mei, H., Wang, Q. et al. Peptide binding specificities of HLA-B*5701 and B*5801. Sci. China Life Sci. 55, 818–825 (2012). https://doi.org/10.1007/s11427-012-4374-z
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DOI: https://doi.org/10.1007/s11427-012-4374-z