Lipid Peroxidation and Hepatitis C Virus Replication

Abstract

Unlike many other positive-strand RNA viruses, replication of hepatitis C virus (HCV) is difficult to achieve in cell culture due to barriers that are not fully understood. An exception to this rule is the JFH1 strain of HCV that atypically replicates robustly without the need for adaptation to cell culture and is therefore widely used in laboratories. Recent studies have revealed that the RNA replicase of most HCV isolates is equipped with a highly sensitive “lipid peroxidation sensor” that shuts off RNA synthesis upon exposure to cellular lipid peroxidation. HCV variants that lack the capacity to be suppressed by lipid peroxidation, such as JFH1 and several highly-adapted viral mutants, are capable of replicating to high levels in cell culture. Thus, adaptive mutations that render the replicase of HCV resistant to lipid peroxidation appear to be a pre-requisite for efficient replication in cell culture. This sensitivity to lipid peroxidation is unique to HCV among other positive-strand RNA viruses that similarly form active RNA replicase complexes derived from host endoplasmic reticulum membranes. This unique regulatory mechanism likely promotes the long-term persistence of HCV by limiting viral exposure to the immune system. This review focuses on the mechanism of lipid peroxidation-mediated regulation of replication in HCV-infected cells, including what is currently known about viral determinants of replication fitness in cell culture and how adaptive mutations in the replicase proteins of HCV alter their interactions with host membranes to determine sensitivity or resistance to lipid peroxidation.