Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.
Highlights
Cells harbor effective antioxidant, detoxifying and cytoprotective mechanisms to maintain cellular homeostasis
This review describes the effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) on reactive oxygen species (ROS)-generating and -inactivating systems with a focus on the interference of these viruses with the Nrf2/antioxidant response element (ARE)-dependent gene expression
For HCV-positive cells there are a variety of reports describing the stimulating effect of HCV on radical producing systems on the one hand and an inhibitory effect on detoxifying systems as the Nrf2/ARE-dependent gene expression
Summary
Cells harbor effective antioxidant, detoxifying and cytoprotective mechanisms to maintain cellular homeostasis. The IRES (internal ribosomal entry site)-mediated translation yields a polyprotein precursor of approximately 3010 amino acids (aa) that is co- and/or post-translationally processed by viral or cellular proteases into 10 mature polyproteins These include the structural proteins core, E1 and E2 and the non-structural (NS) proteins p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B. HCV replication occurs in the cytoplasm in replicon complexes (RCs) at the so-called “membranous web” (MW), a characteristic hallmark of flavivirus-infected cells These virus-induced compartments consist of lipid droplets (LDs) and rearranged ER (endoplasmatic reticulum)-derived membranes including single-, double-, and multi-membrane vesicles that allow a spatiotemporal separation of viral RNA translation, replication and assembly [26,27,28]. Other members of the bZIP protein family are NF-E2 (nuclear factor erythoid 2) p45 [41,42], Nrf (NF-E2 related factor 1) [42,43], Nrf3 [42,44,45], Bach (BTB (Broad-complex, Tramtrack and Bric-à-brac) and CNC homology 1) [42,46] and Bach (BTB and CNC homology 2) [42,47]
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