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.