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

BACKGROUND & AIMS: 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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

IMPACT AND IMPLICATIONS: 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.