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Adaptation of the hepatitis B virus core protein to CD8+ T-cell selection pressure
Helenie Kefalakes1,2, Bettina Budeus3, Andreas Walker1, Christoph Jochum2, Gudrun Hilgard2, Andreas Heinold4, Falko M. Heinemann4, Guido Gerken2, Daniel Hoffmann3 andJoerg Timm5,*
Article first published online: 25 MAR 2015
DOI: 10.1002/hep.27771
Hepatology
Volume 62, Issue 1, pages 47–56, July 2015
Author Information
1 Institute of Virology, University of Duisburg-Essen, University Hospital, Essen, Germany
2 Department of Gastroenterology and Hepatology, University of Duisburg-Essen, University Hospital, Essen, Germany
3 Research Group Bioinformatics, Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
4 Institute for Transfusion Medicine, University of Duisburg-Essen, University Hospital, Essen, Germany
5 Institute for Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany.
*Address reprint requests to: Prof. Dr. Jörg Timm, Heinrich-Heine-Universität Düsseldorf, Universitätsklinikum Düsseldorf, Institut für Virologie, Universitätsstraße 1, 40225 Düsseldorf, Germany. E-mail: [email protected]; tel: +49-211-81 12225; fax: +49-211-81 10792.
Potential conflict of interest: Nothing to report.
Supported by the Deutsche Forschungsgemeinschaft (TRR60 project B1) and by internal funds of the Medical Faculty of the University of Duisburg-Essen.
Publication History
Issue published online: 24 JUN 2015
Article first published online: 25 MAR 2015
Accepted manuscript online: 26 FEB 2015 06:01PM EST
Manuscript Accepted: 25 FEB 2015
Manuscript Received: 27 OCT 2014
Funded by
Deutsche Forschungsgemeinschaft (TRR60 project B1)
Activation of hepatitis B virus (HBV)–specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of covalently closed circular DNA from infected hepatocytes. However, little is known about the exact targets of the CD8 T-cell response and whether HBV reproducibly evades CD8 T-cell immune pressure by mutation. The aim of this study was to address if HBV reproducibly selects substitutions in CD8 T-cell epitopes that functionally act as immune escape mutations. The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection, and the human leukocyte antigen (HLA) class I genotype (A and B loci) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing the novel analysis package SeqFeatR. With this approach we identified nine residues in HBV core under selection pressure in the presence of 10 different HLA class I alleles. Additional immunological experiments confirmed that seven of the residues were located inside epitopes targeted by patients with chronic HBV infection carrying the relevant HLA class I allele. Consistent with viral escape, the selected substitutions reproducibly impaired recognition by HBV-specific CD8 T cells. Conclusion: Viral sequence analysis allows identification of HLA class I–restricted epitopes under reproducible selection pressure in HBV core; the possibility of viral escape from CD8 T-cell immune pressure needs attention in the context of therapeutic vaccination against HBV. (Hepatology 2015;62:47-56)
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发表于 2015-6-28 12:52
