We have recently revealed that cholesterol metabolism in host cells is tightly linked to the life cycle of HCV. We showed that HCV RNA replication can be disrupted by treatment of cells with lovastatin, a cholesterol lowing drug that inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the mevalonate pathway, which is responsible for the cholesterol synthesis in mammalian cells. This inhibition was traced to the depletion of the geranylgeranyl lipid, an isoprenoid produced via the mevalonate pathway. This lipid can be attached to the COOH-terminal cysteine of certain proteins in a post translational modification termed protein geranylgeranylation. We then identified FBL2, a protein of unknown physiological function, as a geranylgeranylated cellular protein required for HCV RNA replication through its interaction with HCV viral protein NS5A.

Another link between HCV infection and cholesterol metabolism in host cells is revealed by our recent discovery that HCV replicates on membrane vesicles involved in the assembly of very low density lipoproteins (VLDL), which is produced in hepatocytes to secret triglyceride and cholesterol. The co-localization of HCV replication and VLDL assembly allows the co-assembly and secretion of HCV and VLDL particles (figure 1). Thus, treatment of cells with agents that specifically block the secretion of VLDL inhibits HCV production at the same time, suggesting that drugs blocking VLDL secretion may be useful in treating HCV infection.