The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of in fected hepatocytes by HBV-specific CD8 cells has been assumed to be the cen tral mechanism causing both liver damage and virus control. To understand t he role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocom patibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex v ivo quantification of circulating and liver-infiltrating HBV-specific CD8 c ells. Two groups of patients with persistent HBV infection were studied: on e without liver inflammation and HBV replication, the other with liver infl ammation and a high level of HBV replication. Contrary to expectation, a hi gh frequency of intrahepatic HBV-specific CD8 cells was found in the absenc e of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute nu mber was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circul ating reservoir of CD8(+) cells able to expand after specific virus recogni tion that was not detectable in highly viremic patients with liver inflamma tion. These results show that in the presence of an effective HBV-specific CD8 re sponse, 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.