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

<jats:title>ABSTRACT</jats:title> <jats:p>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<jats:sup>+</jats:sup>-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 &lt;10<jats:sup>7</jats:sup> copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8<jats:sup>+</jats:sup> T cells are consistently detected. Furthermore, CD8<jats:sup>+</jats:sup> T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8<jats:sup>+</jats:sup> T cells are associated with viral control, while CD8<jats:sup>+</jats:sup> T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (&gt;10<jats:sup>7</jats:sup> copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.</jats:p>