Establishment of chronic hepatitis C virus infection: Translational evasion of oxidative defence

Abstract

Hepatitis C virus (HCV) causes a clinically important disease affecting 3% of the world population. HCV is a single-stranded, positive-sense RNA virus belonging to the genus Hepacivirus within the Flaviviridae family. The virus establishes a chronic infection in the face of an active host oxidative defence, thus adaptation to oxidative stress is key to virus survival. Being a small RNA virus with a limited genomic capacity, we speculate that HCV deploys a different strategy to evade host oxidative defence. Instead of counteracting oxidative stress, it utilizes oxidative stress to facilitate its own survival. Translation is the first step in the replication of a plus strand RNA virus so it would make sense if the virus can exploit the host oxidative defence in facilitating this very first step. This is particularly true when HCV utilizes an internal ribosome entry site element in translation, which is distinctive from that of cap-dependent translation of the vast majority of cellular genes, thus allowing selective translation of genes under conditions when global protein synthesis is compromised. Indeed, we were the first to show that HCV translation was stimulated by an important pro-oxidant-hydrogen peroxide in hepatocytes, suggesting that HCV is able to adapt to and utilize the host anti-viral response to facilitate its own translation thus allowing the virus to thrive under oxidative stress condition to establish chronicity. Understanding how HCV translation is regulated under oxidative stress condition will advance our knowledge on how HCV establishes chronicity. As chronicity is the initiator step in disease progression this will eventually lead to a better understanding of pathogenicity, which is particularly relevant to the development of anti-virals and improved treatments of HCV patients using anti-oxidants.

Keywords: Hepatitis C virus, Oxidative stress, Hydrogen peroxide, Translation, Internal ribosome entry site, Chronicity, Persistence

Core tip: Oxidative stress inhibits canonical translation, however, emerging evidence suggests that oxidative stress can actually stimulate alternative translation from select internal ribosome entry site (IRES) elements including that involved in redox regulation and in persistent virus infection e.g., human immunodeficiency virus and hepatitis C virus (HCV). We postulate a novel role of oxidative stress-activated IRES-mediated translation in redox homeostasis and virus persistence. In the case of HCV, we explore the idea that HCV exploits oxidative stress to activate its own translation as a novel means of evading the host oxidative defence to establish chronicity.