HCV and Oxidative Stress: Implications for HCV Life Cycle and HCV-Associated Pathogenesis

Abstract

HCV (hepatitis C virus) is a member of the Flaviviridae family that contains a single-stranded positive-sense RNA genome of approximately 9600 bases. HCV is a major causative agent for chronic liver diseases such as steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma which are caused by multifactorial processes. Elevated levels of reactive oxygen species (ROS) are considered as a major factor contributing to HCV-associated pathogenesis. This review summarizes the mechanisms involved in formation of ROS in HCV replicating cells and describes the interference of HCV with ROS detoxifying systems. The relevance of ROS for HCV-associated pathogenesis is reviewed with a focus on the interference of elevated ROS levels with processes controlling liver regeneration. The overview about the impact of ROS for the viral life cycle is focused on the relevance of autophagy for the HCV life cycle and the crosstalk between HCV, elevated ROS levels, and the induction of autophagy.

Figure 1

Hypothetical model summarizing the interplay between Nrf2, phosphor-p62, ROS, and autophagy. As described by Carvajal-Yepes et al. [58], Nrf2/ARE-signaling in HCV positive cells is impaired by translocation of sMaf from the nucleus to NS3 in the replicon complexes on the cytoplasmic face of the ER. This leads to the sequestration of Nrf2 to the replicon complex-bound sMaf and prevents the phospho-p62-dependent released Nrf2 from the entry in the nucleus and thereby inhibits the induction of Nrf2/ARE-dependent genes. This would contribute to an impaired elimination of ROS that contribute to the induction of autophagy that is crucial for the HCV life cycle.