Decades after spontaneous HBsAg clearance the CD8+ T cell immune response is less vigorous compared to chronic hepatitis B viral infection

Introduction: Antiviral CD8 T cells are a key component of the adaptive immune response and crucial for the control of hepatitis B viral (HBV) replication. Previous studies analyzing HLA-A*02 restricted CD8-epitopes have shown that patients with spontaneous HBsAg clearance after acute HBV infection have a strong CD8+ T cell immune response, directed against the HBV core protein. Epitopes presented through HLA-B or other HLA-A alleles are not well studied so far. Our objective was to study the CD8+ T cell immune response to HBV core of patients chronically infected as well as decades after spontaneous HBsAg clearance.

Materials and Methods: We evaluated the magnitude of the HBV-specific CD8+ T cell immune response with overlapping peptides for the HBV core protein (Genotype A and D) of 89 patients (36 treatment naive, 53 under nucleot(s)ide analogs) with a chronic HBV infection (HBsAg positive, HBeAg negative) and controlled viremia (HBV-DNA< 2000 IU/ml) and 21 patients after spontaneous HBsAg clearance, after in vitro antigen-specific expansion via flow cytometry. Additionally, all patients were HLA class I typed for characterization of single target epitopes and their HLA-restriction pattern.

Results: Chronically infected, treatment naive patients with controlled viremia have a significantly stronger CD8+ T cell immune response in comparison to patients after spontaneous HBsAg clearance (p = 0.0010) and to patients under nucleotide analogs (p = 0.0021). We identified several novel CD8-epitopes within the HBV core protein which are not presented through HLA-A*02.

Conclusions: Chronically infected treatment naive patients have a stronger immune response in comparison to patients after spontaneous HBsAg clearance and to those under nucleot(s)ide analogs. In contrast to hepatitis C viral infection, the lack of a CD8+ T cell immune response after spontaneous HBsAg clearance may contribute to reactivation under immunosuppressive conditions. Furthermore our results show that so far unidentified epitopes contribute to the HBV-specific CD8+ T cell immune response and a limited approach of only HLA-A*02 presented epitopes is incomplete.