Structural in silico analysis of cross-genotype-reactivity among naturally occurring HCV NS3-1073-variants in the context of HLA-A*02:01 allele

NBLI - Núcleo de Bioinformática do Laboratório de Imunogenética, Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Molecular Immunology (Impact Factor: 2.97). 07/2011; 48(12-13):1461-7. DOI: 10.1016/j.molimm.2011.03.019
Source: PubMed


Cellular immune response plays a central role in outcome of Hepatitis C Virus (HCV) infection. While specific T-cell responses are related to viral clearance, impaired responses can lead to chronic infection, turning HCV variability into a major obstacle for vaccine development. In a recent work, Fytili et al. (2008) studied the cross reactive potential of HCV specific CD8+ T-cells and observed a large variation in immunogenicity among 28 naturally occurring NS3(1073) variants. In this work, we intend to evaluate this immunogenic variation at molecular level, through bioinformatics approaches. The D1-EM-D2 strategy was used to build in silico MHC:peptide complexes (pMHC) of these HCV-derived peptides in the context of HLA-A*02:01 allele. The TCR-interacting surface of these complexes were evaluated using the GRASP2 program. Structural analysis indicated a sharing of topological and electrostatic features among complexes that induced strong response in vitro. Besides, complexes that induced low response presented an important positively charged spot in the center of TCR-interacting area. This spot was seen even in complexes with conservative amino acid changes and is consistent with the impairment of recognition by wild-type-specific T-cells, observed in vitro. Furthermore, the most remarkable difference in electrostatic potential was seen precisely in the only complex unable to induce in vitro stimulation. All these observations were confirmed by Principal Component Analysis (PCA) and this approach was also applied to a set of 45 non-related immunogenic viral epitopes, indicating possible new targets for cross-reactivity studies. Our results suggest structural in silico analysis of pMHC complexes as a reliable tool for vaccine development, affording to predict the impact of viral escape mutations and selection of epitopes with potential to induce cross-reactive immune responses.

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    • "The visual inspection revealed a striking similarity between them, evidencing the reliability of this kind of investigation. Here, we extended a previous study (20) and analysed 60 unrelated pMHC-I complexes presenting virus-derived peptides, in the context of the most frequent human MHC allele (HLA-A*02:01). These complexes, 5 crystal structures and 55 in silico predicted structures, were obtained from the CrossTope. "
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    ABSTRACT: The CrossTope is a highly curate repository of three-dimensional structures of peptide:major histocompatibility complex (MHC) class I complexes (pMHC-I). The complexes hosted by this databank were obtained in protein databases and by large-scale in silico construction of pMHC-I structures, using a new approach developed by our group. At this moment, the database contains 182 ‘non-redundant’ pMHC-I complexes from two human and two murine alleles. A web server provides interface for database query. The user can download (i) structure coordinate files and (ii) topological and charges distribution maps images from the T-cell receptor-interacting surface of pMHC-I complexes. The retrieved structures and maps can be used to cluster similar epitopes in cross-reactivity approaches, to analyse viral escape mutations in a structural level or even to improve the immunogenicity of tumour antigens. Database URL:
    Database The Journal of Biological Databases and Curation 01/2013; 2013:bat002. DOI:10.1093/database/bat002
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    ABSTRACT: This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) heterologous immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and heterologous immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols? © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail:
    Transactions of the Royal Society of Tropical Medicine and Hygiene 01/2015; 109(1):62-69. DOI:10.1093/trstmh/tru198
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    ABSTRACT: T cell responses play a critical role in controlling or clearing viruses. Therefore, strategies to prevent or treat infections include boosting T cell responses. T cells specific for various pathogens have been reported in unexposed individuals and an influence of such cells on the response toward vaccines is conceivable. However, little is known about their frequency, repertoire, and impact on vaccination.We performed a detailed characterization of CD8+ T cells specific to a hepatitisCvirus (HCV) epitope (NS3-1073) in 121 HCV-seronegative individuals.Weshow that in vitroHCVNS3-1073-specific CD8+ T cell responses were rather abundantly detectable in one-third of HCV-seronegative individuals irrespective of risk factors forHCVexposure. Ex vivo, these NS3-1073-specific CD8+ T cells were found to be both naive and memory cells. Importantly, recognition of various peptides derived from unrelated viruses by NS3-1073- specific CD8+ T cells showed a considerable degree of T cell cross-reactivity, suggesting that they might in part originate from previous heterologous infections. Finally, we further provide evidence that preexisting NS3-1073-specific CD8+ T cells can impact the T cell response toward peptide vaccination. Healthy, vaccinated individuals who showed an in vitro response toward NS3-1073 already before vaccination displayed a more vigorous and earlier response toward the vaccine.
    Journal of Virology 06/2015; 89(16). DOI:10.1128/JVI.00539-15
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Questions & Answers about this publication

  • Dinler Antunes added an answer in Bioinformatic Tools:
    How can I visualise the structures of HLA alleles?

    I have a couple of peptides (epitopes) with corresponding HLA alleles. Any possibility that I can visualise the structure of HLA alleles along with the bound epitope and to see how the epitope is accommodated in side the pocket utilising some bioinformatic tools? 

    Dinler Antunes

    As discussed above by Maurício, you cannot just "align" your desired peptide in the cleft of a given MHC allele, the structure would not be reliable. There is one webserver to provide initial structures of desired pMHC complexes, MHCSim, but these structures are obtained by mutating available crystal structures and need to be further refined after modeling. 

    There are other prediction methods already described, such as D1-EM-D2 and pDOCK. The D1-EM-D2 was developed by our group and was used to make structure-based predictions on T cell cross-reactivity. It was also used to model several complexes presenting virus-derived epitopes, which are avaliable through the CrossTope Data Bank. Maybe your complexes of interest were already predicted using our approach. 

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