Discovery of conserved HDV-specific CD8+ T-cell epitopes in HBV/HDV infection

Background and aims Hepatitis D virus (HDV) super-infection of hepatitis B virus (HBV)-infected patients is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. The virus-specific CD8+ T-cell response is thought to have a major impact on the outcome of HDV infection. However, the HDV-specific T-cell epitope repertoire is only poorly characterized and mechanisms contributing to T-cell failure during chronic infection are not yet fully understood. Previously, we identified HDV-specific CD8+ T-cell epitopes in regions of the large HD antigen (L-HDAg) in which the HDV tolerates mutations to escape immune recognition. In this study, we aimed to discover T-cell epitopes that are located in conserved regions, in order to characterize the influence of these T cells on infection outcome.

Methods PBMC from 19 chronic and 15 resolved HBV/HDV infected patients were stimulated with an overlapping peptide (OLP) pool covering the L-HDAg. After in vitro expansion virus-specific CD8+ T cells were detected by intracellular cytokine staining. For positive responses, HLA restriction and epitope fine-mapping were defined. Tetramers were generated for detection of HLA-B*08:01 restricted HDV-specific CD8+ T cells.

Result Interferon gamma (IFNγ) secretion of CD8+ T cells in response to peptide pool re-stimulation was detected in 52.6 % of HDV RNA+ patient, whereas 66.6 % of HDV RNA- patients responded to at least one peptide pool. OLP-specific CD8+ T cells predominantly co-secreted IFNγ and tumor necrosis factor (TNF). In agreement with our previous findings, novel epitopes were nearly exclusively restricted by rare HLA-B alleles. As an exception, the more common allele HLA-B*08:01 restricted an epitope highly conserved in genotype 1. Responses against this epitope were detectable by tetramer staining ex vivo.

Conclusion We were able to further expand the known HDV-specific-CD8+ T-cell epitope repertoire. Importantly, we also identified an epitope that is located in a highly conserved virus region and restricted by a relatively common HLA class I allele. This epitope may allow further insights into the fate and function of HDV-specific CD8+ T cells in the natural as well as treatment-associated course of HBV/HDV infection.

Publication History

Article published online:
04 January 2021