Dominance of HLA-B restricted virus-specific CD8+ T cell epitopes in chronic HBV infection

Abstract

Background and Aims: HBV-specific CD8+ T cells are essential for HBV clearance and are an attractive target for immunotherapeutic intervention. However, the HBV-specific CD8+ T cell repertoire is poorly characterized. Indeed, <10 HLA-B restricted HBV-specific CD8+ T cell epitopes are described to date, although recent findings in the field of HIV and HCV infection clearly demonstrate a dominant role of these epitopes. We therefore aimed to identify novel CD8+ T-cell epitopes in HBV-infection and also address the relative contribution of HLA-A versus HLA-B restricted epitopes. Methods: 30 patients with chronic HBV (genotype D) and low viremia were screened for HBV-specific CD8+ T-cell responses using overlapping peptides spanning all HBV proteins in a matrix setup in an elispot assay. Positive responses were confirmed by intracellular interferon gamma staining, optimal epitopes were fine-mapped and HLA restriction was determined. In addition, the autologous viral sequences corresponding to the identified epitopes were analyzed in the patients. Results: 10 out of 30 patients targeted at least one CD8+ T cell epitope (range: 1–10). In total, we identified 27 CD8+ T cell responses. Interestingly, responses targeted core, polymerase and X proteins, but completely spared the surface antigen. None of these responses targeted previously described HBV-specific CD8+ T cell epitopes. To date, we were able to fine-map 10 novel CD8+ T cell epitopes. Importantly, most of these epitopes were restricted by HLA-B alleles (4 x HLA-B*35; 2 x HLA-B*7; 1 x HLA-B*14; 1 x HLAB*15). In one epitope restricted by HLA-B*35:02 we found evidence for the selection of viral escape mutations. Conclusions: In our cohort, HBV-specific CD8+ T cell responses are dominantly restricted by HLA-B alleles. These findings indicate that previous studies on HBV-specific immunity mainly focussing e.g. on HLA-A*02 restricted CD8+ T cell epitopes may not necessarily be conferrable to the complete CD8+ T cell repertoire. They also suggest that HLA-B restricted CD8+ T cell epitopes may be important targets for immunotherapy. The absence of T-cell responses located in the surface-Protein implies a dominant role of the HBs antigen in immune regulation and persistence of HBV.