Skewed HBV-specific CD8+T cell repertoire in chronic versus acute-resolving HBV infection

Background/aims: Function and quantity of CD8+T cell responses is superior in acute-resolving versus chronic HBV infection. If epitopes are targeted differentially in these outcomes of HBV infection, is unclear.

Methods: PBMC from 80 patient with HBV infection (55 chronic; 25 resolved or acute) were screened for interferon-ɣ responses using overlapping peptides covering the full HBV proteome. Subsequent epitope fine-mapping and HLA-restriction analysis was performed. Additionally, autologous viral sequences of the tested and additional patients with chronic HBV infection (overall n=532) were obtained.

Results: We found a broad HBV-specific CD8+T cell epitope repertoire in acute HBV infection. After spontaneous resolution, the number of these responses decreased, while the broad landscape was preserved. In chronic HBV infection, the HBV-specific CD8+T cell epitope repertoire was skewed, with a lack of functional HBsAg-specific CD8+T cell responses, as recently described. HBx-specific responses were relatively over-represented. Interestingly, patients with chronic HBV infection showed significantly more HLA-B- than HLA-A-restricted HBV-specific CD8+T cell responses, while the distribution in acute-resolving HBV infection was balanced. This might be explained by T cell selection pressure. Compared to HLA-A-restricted CD8+T cell responses, HLA-B restricted responses more frequently displayed autologous viral sequences variations indicating viral escape. This trend was validated in a broader sequence dataset, where HLA-associated viral footprints were more frequently detected for HLA-B compared to HLA-A.

Conclusions: HLA-B-restricted epitopes are dominant in chronic HBV infection, but might be more prone to viral escape. This findings have implications for the development of future immunotherapeutic approaches.

Publication History

Article published online:
20 January 2025