Most studies have focused on the direct cytopathic effects of individual HCV proteins, with the objective of identifying their specific roles in the overall pathogenesis. However, this approach precludes examination of the possible interactions between different HCV proteins and organelles. We hypothesize that different components of HCV polyprotein, depending on their subcellular distributions, cause different types of cytopathic effects and elicit different types of responses in different subcellular compartments. To obtain a better understanding of the various cytopathic effects of and cellular responses to HCV proteins, we used hepatoma cells constitutively expressing the HCV genomelength replicon, the subgenomic replicon, or the core protein to model the state of persistent HCV infection and took a comparative approach to dissecting the role of various HCV proteins in cellular pathogenesis in this study.