Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus

Abstract

Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, infects more than 170 million people worldwide and is the leading cause of liver failure in the United States. A unique feature of HCV is that the viral life cycle depends on cholesterol metabolism in host cells. This review summarizes the cholesterol metabolic pathways that are required for the replication, secretion, and entry of HCV. The potential application of drugs that alter host cholesterol metabolism in treating HCV infection is also discussed.

Figure 1. Requirement of the Mevalonate Pathway for HCV Replication

Cells are capable of synthesizing cholesterol through the mevalonate pathway. This pathway also produces geranylgeranyl lipid, which is attached to the COOH-terminus of FBL2. Geranylgeranylated FBL2 binds to NS5A, an interaction required for HCV RNA replication. Lovastatin, an inhibitor of HMG CoA reductase, blocks the entire mevalonate pathway. As a result, cells are depleted of geranylgeranyl lipid and replication of HCV is inhibited. PP, pyrophosphate.

Figure 2. HCV Replicates on ER Membranes Involved in the Assembly of VLDL and Is Secreted Together with VLDL

The assembly of VLDL begins with the synthesis of apoB in the rough ER, resulting in the formation of a VLDL precursor that contains only a small amount of lipid. In the lumen of the ER, this precursor is fused with lipid droplets (enriched in triglyceride and cholesterol) to generate nascent VLDL. This reaction is mediated by MTP. The nascent VLDL particles, which contain both apoB and apoE, are secreted into plasma through exocytosis. The ER membranes involved in the assembly of VLDL are also enriched in HCV NS proteins and RNA. Replication of HCV on these membranes might allow the virus to attach to or become incorporated into VLDL so that HCV is secreted together with VLDL.