Robust HLA-B-restricted CD8+ T-cell responses in chronic HBV infection

The function and quantity of CD8+ T-cell responses is superior in acute vs. chronic HBV infection. However, whether different HBV-derived epitopes are targeted in these distinct courses of HBV infection remains unclear.

We screened peripheral blood mononuclear cells from 56 patients with chronic HBV infection genotype D and 32 patients with acute/resolved HBV infection to identify responses to overlapping peptides (18mers) covering the full HBV genotype D proteome. We then performed experimental fine-mapping of the minimal optimal epitopes.

Patients with acute HBV infection showed a broad HBV-specific CD8+ T-cell epitope repertoire. After spontaneous resolution, the strength of HBV-specific CD8 T-cell responses decreased, whereas the broad epitope landscape was preserved. In chronic HBV infection, the specificity of HBV-specific CD8+ T-cell responses to HBV antigens was shifted, with a lack of functional HBsAg-specific CD8+ T-cell responses (p = 0.0007), as recently described. Interestingly, patients with chronic HBV infection showed significantly more HLA-B-restricted HBV-specific CD8+ T-cell responses than HLA-A-restricted responses (33 vs. 19), whereas this distribution was balanced in patients with acute/resolved HBV infection (16 vs. 27; p = 0.0364). Most (79.6%) of the detected responses showed conserved autologous viral sequences. This observation was confirmed in a broader sequence dataset with no evidence for HLA-B-driven CD8+ T-cell selection pressure.

In contrast to acute/resolved infection, conserved HLA-B-restricted epitopes are dominant in chronic HBV infection, making them interesting candidates for immunotherapeutic approaches towards functional cure of chronic HBV infection.

To date, there is no treatment to achieve functional cure of chronic HBV infection. Immunotherapy boosting dysfunctional HBV-specific CD8+ T cells is an interesting approach, but relies on selection of optimal target epitopes. Using an unbiased approach, we found that the HBV-specific CD8+ T-cell epitope repertoire in chronic HBV infection is not well covered by previously described epitopes. We characterized 28 novel, primarily HLA-B-restricted epitopes that are dominantly targeted in chronic HBV infection. These might be used as a "toolbox" for immunological studies and immunotherapeutic approaches.