Comprehensive analysis of the intrahepatic virus-specific CD8+ T-cell response during chronic hepatitis C virus infection

Abstract

In order to define the actual breadth and magnitude of the virus-specific CD8+-T-cell response during chronic hepatitis C virus infection, we have studied this response in the liver and blood by using a set of 441 overlapping peptides spanning the entire HCV polyprotein. Peptides identified in screening ELISPOTs were further tested by intracellular IFNγ staining. Multispecific virus-specific CD8+-T-cell responses were detectable in most chronically infected patients, targeting an average of three different epitopes. Importantly, all epitope-specific CD8+-T-cell responses detectable in the blood were also present in the liver, indicating a strong overlap between the peripheral and intrahepatic T-cell response. Indeed, HCV-specific responses were enriched in the liver and there were additional responses identified intrahepatically. These results indicate that neither a lack of homing of virus-specific T-cells to the liver nor a rapid deletion of virus-specific T-cells in the liver contribute substantially to viral persistence. Interestingly, most responses detected in our study were directed against previously uncharacterized epitopes, demonstrating the heterogenity and multispecificy of virus-specific T-cell responses and the lack of a clear immunodominance in HCV infection.