HDV superinfection of chronic hepatitis B leads to rapid progression of liver cirrhosis, but the mechanisms that drive disease pathogenesis are not known. HDV-specific T cells have not been detected in chronic patients and only very few CD8 T cell epitopes were identified in rare recovered patients. Reasoning that a surge in viremia after lonafarnib/ritonavir antiviral therapy may boost T cell responses and facilitate epitope mapping in chronic HDV infection, we established HDV-specific T cell lines from post-treatment bleeds of chronic HDV patients and mapped CD8 T cell epitopes with pools of overlapping HDV peptides and dose titrations of 15-mer and shorter peptides. IFN-gamma production was used as read-out. With this approach, we identified six CD8 T cell epitopes, several of which were restricted by multiple HLA class I alleles. These were used to synthesize MHC-epitope multimers and to characterize HDV-specific CD8 T cells ex vivo in untreated patients. HDV-specific CD8 T cells were as frequent as HBV-specific CD8 T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8 T cells correlated with aminotransferase activity as a biomarker for liver inflammation. CD8 T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8 T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein Barr virus-specific CD8 T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8 T cells had a memory-like PD1+CD127+TCF1-high Tbet-low phenotype, which associated with HDV sequence variants with reduced HLA-binding and reduced T-cell activation. In conclusion, we have shown that CD8 T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8 T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8 T cells is functional but unable to clear HDV because of the presence of viral escape variants.
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