Huh7 cells with the subgenomic replicon showed significant upregulation of multiple antioxidant enzymes that belonged to the cytosolic and mitochondrial compartments ( Figure 5 ). Despite the up-regulation of multiple antioxidant enzymes, the ratios of oxidized (Sulfonic form) to total peroxiredoxin 1 and 3 in the subgenomic replicon cells remained the same as that in Huh7 cells ( Figure S5 ), suggesting that the overall redox environment was still more oxidizing. This conclusion was also supported by the increased MitoSOX staining and reduced aconitase activities ( Figures 2C and 2D and Figure S3B ). Whether the up-regulation of multiple antioxidant enzymes in the subgenomic replicon cells is a direct response to the presence of HCV non-structural proteins or is merely a clonal variation will need to be deciphered with additional studies in the future. However, it is worth noting that previous studies with different HCV subgenomic repliconexpressing cells also showed a similar up-regulation in various antioxidant enzymes [17, 44] . Huh7 cells with the genome-length replicon had a 1.8-fold increase in the mitochondrial form of thioredoxin (TRX2), but a 15% reduction of its upstream enzyme PRDX3 ( Figure 5 ). The net result was a slightly higher ratio of PRDX3-SO3 to total PRDX3; however, the increase was not significantly higher than that of Huh7 cells ( Figure S5B ). The expression level of non-structural proteins should be comparable between the genome-length and subgenomic replicon cells based on the SEAP reporter assay ( Figure S1A ) and published results [45] . Therefore, the lack of antioxidant response in cells with the genome-length replicon was probably not due to a difference in the expression of non-structural proteins; but rather, it could be due to the additional cytopathic effects from core, E1, E2, and p7 proteins that counteract the antioxidant enzyme response induced by non-structural proteins. Consequently, the genome-length replicon cells had a prolonged population doubling time and reduced cyclin D1 expression (Figure 6) , which suggested delayed cell cycle progression. In contrast, Core-on cells showed no changes in any of the antioxidant enzymes examined.