Abstract
Replication of the hepatitis C virus (HCV) strongly relies on various lipid metabolic processes in different steps of the viral life cycle. In general, HCV changes the cells’ lipidomic profile by differentially regulating key pathways of lipid synthesis, remodeling, and utilization. In this review, we sum up the latest data mainly from the past five years, emphasizing the role of lipids in HCV RNA replication, assembly, and egress. In detail, we highlight changes in the fatty acid content as well as alterations of the membrane lipid composition during replication vesicle formation. We address the role of lipid droplets as a lipid provider during replication and as an essential hub for HCV assembly. Finally, we depict different ideas of HCV maturation and egress including lipoprotein association and potential secretory routes.
Highlights
Replication of the hepatitis C virus (HCV) strongly relies on various lipid metabolic processes in different steps of the viral life cycle
The “old” NS5A-positive membranous structures are the main target for cholesterol delivery and associate with lipid droplets (LDs) and the HCV core protein, whereas the “new” structures are formed de novo at distinct sites that facilitate the interaction between NS5A and the phosphatidylinositol 4-kinase (PI4KA) as well as the oxysterol-binding protein (OSBP) that both play crucial roles for efficient double membrane vesicle (DMV) formation during HCV infection
Mutations in ABHD5 can cause the Chanarin-Dorman syndrome, a lipid storage disorder in humans [45]. These ABHD5 Chanarin-Dorfman mutants do not localize to LDs or support LD lipolysis or HCV replication, suggesting that the proviral function of ABHD5 depends on its lipase cofactor function
Summary
Apart from being essential building blocks for cellular lipids, fatty acids (FAs) are involved in cellular signaling pathways and posttranslational protein modification. It was shown that a cell culture-adapted version of JFH1, that generally promotes HCV particle production and increases infectivity compared to the wildtype, reduces SM secretion, likely due to a decreased SM content in the virions [19]. This is dependent on the interaction between NS5B and p7 carrying specific cell culture-adapted mutations, in the case of NS5B within the SM-binding pocket. These data underline the importance of the interaction between viral proteins and host lipids to regulate viral infectivity
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