title: Improved structural method for T-cell cross-reactivity prediction.
abstract: Cytotoxic T-lymphocytes (CTLs) are the key players of adaptive cellular immunity, being able to identify and eliminate infected cells through the interaction with peptide-loaded major histocompatibility complexes class I (pMHC-I). Despite the high specificity of this interaction, a given lymphocyte is actually able to recognize more than just one pMHC-I complex, a phenomenon referred as cross-reactivity. In the present work we describe the use of pMHC-I structural features as input for multivariate statistical methods, to perform standardized structure-based predictions of cross-reactivity among viral epitopes. Our improved approach was able to successfully identify cross-reactive targets among 28 naturally occurring hepatitis C virus (HCV) variants and among eight epitopes from the four dengue virus serotypes. In both cases, our results were supported by multiscale bootstrap resampling and by data from previously published in vitro experiments. The combined use of data from charges and accessible surface area (ASA) of selected residues over the pMHC-I surface provided a powerful way of assessing the structural features involved in triggering cross-reactive responses. Moreover, the use of an R package (pvclust) for assessing the uncertainty in the hierarchical cluster analysis provided a statistical support for the interpretation of results. Taken together, these methods can be applied to vaccine design, both for the selection of candidates capable of inducing immunity against different targets, or to identify epitopes that could trigger undesired immunological responses.
authors.affiliation: NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Building 43323, room 225, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: marcus.famendes@gmail.com.
authors.forename: Marcus F A
authors.initials: MF
authors.lastname: Mendes
authors.affiliation: NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Building 43323, room 225, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil; Department of Computer Science, Rice University, Houston, Texas, 77005, USA. Electronic address: dinler@gmail.com.
authors.forename: Dinler A
authors.initials: DA
authors.lastname: Antunes
authors.affiliation: NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Building 43323, room 225, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: mauriciomr985@gmail.com.
authors.forename: Maurício M
authors.initials: MM
authors.lastname: Rigo
authors.affiliation: NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Building 43323, room 225, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: msinigaglia@gmail.com.
authors.forename: Marialva
authors.initials: M
authors.lastname: Sinigaglia
authors.affiliation: NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, Building 43323, room 225, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: gusfioravanti@yahoo.com.br.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Vieira
mesh_terms: D016000:Cluster Analysis; D017124:Conserved Sequence; D003429:Cross Reactions / Q000276:immunology*; D018360:Crystallography, X-Ray; D053059:Dengue Vaccines / Q000276:immunology; D003716:Dengue Virus / Q000145:classification / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015203:Reproducibility of Results; D012703:Serotyping; D055672:Static Electricity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D053059:Dengue Vaccines; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: ASA; Cross-reactivity; HCA; Pvclust; Vaccine development; pMHC-I