Differential escape pathways from the dominant CD8 T cell epitope in HBV core18 – 27 depend on the HLA class I genotype

The CD8 T cell response plays a central role for spontaneous immune control of acute Hepatitis B Virus (HBV) infection. In turn, patients with chronic infection typically have a weak and often exhausted T cell response. Accordingly, rescue of such dysfunctional T cell responses by therapeutic vaccination or transfer of adaptive cytotoxic T cells has been suggested as potential treatment strategies of patients with chronic infection. Importantly, these therapies rely on presentation of viral epitopes in the context of HLA class I molecules. Although selection of viral escape mutations has been well defined in chronic infections with HCV or HIV, the influence of viral sequence variants on the T cell response in HBV is less clear. Here, we studied viral sequence diversity in the HLA-A*02-restricted immunodominant HBV CTL epitope core_{18 – 27} (FLPSDFFPSV) and its impact on the CD8 T cell response in detail.

As previously described, the epitope core_{18 – 27} was targeted in the context of multiple HLA class I alleles, including HLA-A*02:01, HLA-B*51 and HLA-B*35:01/03. Notably, HLA-restriction was subtype-specific and in hosts carrying multiple relevant HLA class I alleles different alleles contributed to the CD8 T cell response. Analysis of 291 HBV core sequences revealed extensive sequence variation in the epitope region. Importantly, there was strong evidence for selection of a F24Y and V27I mutation in HLA-A*02:01-positive individuals. In contrast, patients presenting the same epitope in the context of HLA-B35:01/03 selected a S21A mutation. Interestingly, despite selection of sequence variants in the epitope region, antigen-specific CD8 T cells had unexpected high levels of memory marker CD127 and showed a high degree of cross-reactivity, which is not consistent with functional immune escape. We therefore hypothesized, that presentation of the endogenously processed epitope is impaired. Indeed, when the variant carrying the F24Y substitution was endogenously processed in the context of HLA-A*02:01, the CD8 T cell response was severely impaired consistent with HBV escape from the CD8 T cell response by altered epitope processing.

We conclude that depending on the presenting HLA class I molecule different escape pathways are selected in the immunodominant HBV epitope core_18–27. A F24Y substitution in the context of HLA-A*02:01 impairs antigen processing and presentation. Accordingly, immune therapies targeting this epitope variant are predicted to be ineffective. Analysis of autologous viral sequences will be important when T cell-based therapies are considered.