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

Area of Science:

• Immunology
• Virology
• Hepatology

Background:

• Hepatitis B virus (HBV) infection can be acute or chronic, with distinct CD8+ T cell response profiles.
• Understanding HBV-specific CD8+ T cell epitope targeting is crucial for developing effective immunotherapies.
• Previous studies suggest functional and quantitative differences in CD8+ T cell responses between acute and chronic HBV infection.

Purpose of the Study:

• To investigate the differences in HBV-derived CD8+ T cell epitope targeting between acute and chronic HBV infection.
• To identify novel HBV epitopes relevant for immunotherapeutic strategies in chronic HBV infection.

Main Methods:

• Screening of peripheral blood mononuclear cells (PBMCs) from patients with chronic HBV genotype D and acute/resolved HBV infection using overlapping peptides covering the HBV genotype D proteome.
• Fine-mapping of minimal optimal epitopes to comprehensively characterize the CD8+ T cell response landscape.
• Analysis of HLA restriction (HLA-A vs. HLA-B) and conservation of targeted viral sequences.

Main Results:

• Acute HBV infection elicits a broad HBV-specific CD8+ T cell epitope repertoire, which is largely preserved after resolution, although response strength diminishes.
• Chronic HBV infection is characterized by a shift in epitope specificity, notably a lack of functional HBsAg-specific CD8+ T cell responses.
• A significantly higher proportion of HLA-B-restricted CD8+ T cell responses were observed in chronic HBV infection compared to acute/resolved infection.
• 28 novel, predominantly HLA-B-restricted epitopes were identified as dominant targets in chronic HBV infection, with high conservation in autologous viral sequences.

Conclusions:

• Conserved HLA-B-restricted epitopes are dominant in chronic HBV infection, contrasting with the broader epitope targeting in acute/resolved infection.
• These identified epitopes represent valuable targets for developing immunotherapeutic approaches aimed at achieving a functional cure for chronic HBV infection.
• The characterized epitope repertoire provides a toolbox for further immunological studies and the development of novel HBV immunotherapies.