Longitudinal Analysis of CD8+T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy

ABSTRACT The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8 + -T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <10 7 copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8 + T cells are consistently detected. Furthermore, CD8 + T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8 + T cells are associated with viral control, while CD8 + T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>10 7 copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.