Exploitation of lipid components by viral and host proteins for hepatitis C virus infection

Abstract

Hepatitis C virus (HCV), which is a major causative agent of blood-borne hepatitis, has chronically infected about 170 million individuals worldwide and leads to chronic infection, resulting in development of steatosis, cirrhosis, and eventually hepatocellular carcinoma. Hepatocellular carcinoma associated with HCV infection is not only caused by chronic inflammation, but also by the biological activity of HCV proteins. HCV core protein is known as a main component of the viral nucleocapsid. It cooperates with host factors and possesses biological activity causing lipid alteration, oxidative stress, and progression of cell growth, while other viral proteins also interact with host proteins including molecular chaperones, membrane-anchoring proteins, and enzymes associated with lipid metabolism to maintain the efficiency of viral replication and production. HCV core protein is localized on the surface of lipid droplets in infected cells. However, the role of lipid droplets in HCV infection has not yet been elucidated. Several groups recently reported that other viral proteins also support viral infection by regulation of lipid droplets and core localization in infected cells. Furthermore, lipid components are required for modification of host factors and the intracellular membrane to maintain or up-regulate viral replication. In this review, we summarize the current status of knowledge regarding the exploitation of lipid components by viral and host proteins in HCV infection.

Keywords: HCV; hepatitis; host factor; lipid droplets.

Figure 1

Structure of HCV. HCV RNA encodes a polyprotein composed of about 3,000 amino acids. The core protein, and two envelope proteins are classified as structural protein, while NS2, NS3, NS4A, NS4B, NS5A, and NS5B are non-structural proteins.

Figure 2

The infection cycle of HCV. The HCV complex with VLDL binds to entry factors on the surface of hepatocytes and then enters cells by endocytosis. After uncoating, viral replication is carried out in the convoluted membrane structure called the membranous web. The viral nucleocapsid egresses into the lumen side of the ER and binds to VLDL. The HCV complex with VLDL is released from the infected cells.

Figure 3

Hepatitis C virus RNA replication and particle production on lipid droplets and the ER membrane. HCV RNA replication and viral particle production are thought to be carried out on the lipid droplets and ER membrane. The viral proteins take advantage of host lipid metabolism and intracellular compartments to produce viral components as described in the text. Each step is described below. (1) A newly synthesized or uncoated vial genomic RNA is translated to a viral polyprotein followed by a cleaving polyprotein. (2) Matured non-structural proteins form replication a complex with host factors. The core protein is translocated to lipid droplets by DGAT1. In cells infected with the highly infectious strain (e.g., Jc1), the core protein may be retained on ER membrane by cooperating with non-structural proteins. (3) NS4B is involved in the convoluted membrane structure dubbed the membranous web. Negative and positive strands of viral RNA are synthesized by the replication complex based on each other. (4) The positive strand of genomic RNA is enclosed with the core proteins, cooperating non-structural proteins. Envelope proteins, NS2, and p7 may determine recruitment of the core protein from lipid droplets to the ER membrane along microtubules. Lipid droplets hemi-fused with ER membrane (Wolins et al., 2006) may be involved in recruitment of core protein on the ER membrane (4′). (5) The core proteins enclose the viral RNA genome, and are then surrounded by envelopes. Non-structural proteins and other factors may support formation of nucleocapsid and budding. (6) VLDL binds to viral particles to form LVP before or after budding. (7) The viral particles egress into the ER lumen with VLDL including ApoE. The core protein upregulates synthesis or storage of triglycerides and cholesteryl ester, cooperating with host factors including DGAT1, and so on.