Effect of the infectious dose and the presence of hepatitis C virus core gene on mouse intrahepatic CD8 T cells.

Aim: Chronic hepatitis C viral (HCV) infections often result in ineffective CD8 T-cell responses due to functional exhaustion of HCV-specific T cells. However, how persisting HCV impacts CD8 T-cell effector functions remains largely unknown. The aim of this study is to examine the effect of the infectious dose and the presence of HCV core gene. Methods: We compared responses of intrahepatic CD8 T cells during infection of wild-type or HCV core transgenic (Tg) mice with various infectious doses of HCV-NS3-expressing recombinant adenovirus (Ad-HCV-NS3). Results: Using major histocompatibility complex class I tetramer and intracellular interferon (IFN)-gamma staining method to track HCV-NS3-specific CD8 T cells, we found that a significant expansion of HCV-NS3-specific CD8 T cells was restricted to a very narrow dosage range. IFN-gamma production by intrahepatic CD8 T cells in HCV core Tg mice was suppressed as compared with wild-type mice. Higher levels of expression of regulatory molecules, Tim-3 and PD-1, by intrahepatic CD8 T cells and PD-L1 by intrahepatic antigen-presenting cells were observed in HCV core Tg mice following Ad-HCV-NS3 infection, and the expression increased dependent on infectious dose. Furthermore, we found a significant inverse correlation between the percentages of IFN-gamma producing cells and expression of regulatory molecules in antigen-specific intrahepatic CD8 T cells. Conclusion: High infectious dose and the presence of HCV core gene were strongly involved in ineffective CD8 T-cell responses. We consider that HCV core Tg mouse infected with high infectious dose of Ad-HCV-NS3 is useful as a chronic infection model in the development of immunotherapy for chronic hepatitis C.