کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2831233 1570736 2011 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structural in silico analysis of cross-genotype-reactivity among naturally occurring HCV NS3-1073-variants in the context of HLA-A*02:01 allele
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شناسی مولکولی
پیش نمایش صفحه اول مقاله
Structural in silico analysis of cross-genotype-reactivity among naturally occurring HCV NS3-1073-variants in the context of HLA-A*02:01 allele
چکیده انگلیسی

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 NS31073 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Immunology - Volume 48, Issues 12–13, July 2011, Pages 1461–1467
نویسندگان
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