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J Virol. 2019 Dec 18. pii: JVI.01663-19. doi: 10.1128/JVI.01663-19. [Epub ahead of print]
Discovery and selection of HBV-derived T cell epitopes for global immunotherapy based on viral indispensability, conservation and HLA-binding strength.
de Beijer MTA1, Jansen DTSL1, Dou Y1, van Esch WJE2, Mok JY2, Maas MJP2, Brasser G2, de Man RA1, Woltman AM1, Buschow SI3.
Author information
1
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, the Netherlands.
2
Sanquin, Amsterdam, the Netherlands.
3
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, the Netherlands [email protected].
Abstract
Immunotherapy represents an attractive option for the treatment of chronic Hepatitis B virus (HBV) infection. HBV proteins Polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA-supertypes prevalent in HBV-infected patients. Potential epitopes expected to be least prone to immune escape were subjected to a state-of-the-art in vitro assay to validate HLA-binding capacity. Using this method, a total of 13 HLA-binders derived from HBx and 33 binders from Pol were identified across HLA-types. Subsequently, we demonstrated IFNγ production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design.Importance Multiple HBV-derived T cell epitopes have been reported which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA-supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets which are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for development of globally effective HBV-antigen-specific immunotherapies.
Copyright © 2019 de Beijer et al.
PMID:
31852786
DOI:
10.1128/JVI.01663-19
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发表于 2019-12-21 15:27