Role of Core Protein-Induced Oxidative Stress in the Pathogenesis of Hepatitis C

Summary

Chronic infection with the Hepatitis C virus results in slowly progressive liver injury characterized by hepatic necroinflammation, progressive fibrosis, and hepatocellular carcinoma. Liver injury results from a combination of immunemediated and direct viral effects. The HCV core protein has been shown to produce oxidative stress when overexpressed in multiple different cell lines as well as in the livers of transgenic mice. The mechanisms of core-induced oxidative stress are not certain, but core protein partially localizes in mitochondria and thus may alter mitochondrial respiration resulting in an increased production of reactive oxygen species. Core-induced oxidative stress produces different consequences in different cell types. In Huh-7 human hepatoma cells, it results in increased lipid peroxidation and induction of antioxidant gene expression. Potential pathological consequences of core-induced oxidative stress include DNA damage, lipid peroxidation, cell cycle dysregulation, and stellate cell activation. These in turn contribute to cell death, fibrogenesis, and carcinogenesis, as seen in patients with chronic hepatitis C. Modulation of oxidative stress may therefore have the potential to modify the clinical course of hepatitis C.