Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes
by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver
damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of
HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with
persistent HBV infection were studied: one without liver inflammation and HBV replication,
the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular
infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a
circulating reservoir of CD81 cells able to expand after specific virus recognition that was not
detectable in highly viremic patients with liver inflammation.
These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.