Abstract
The replication cycle of the liver-tropic hepatitis C virus (HCV) is tightly connected to the host lipid metabolism, during the virus entry, replication, assembly and egress stages, but also while the virus circulates in the bloodstream. This interplay coins viral particle properties, governs viral cell tropism, and facilitates immune evasion. This review summarizes our knowledge of these interactions focusing on the late steps of the virus replication cycle. It builds on our understanding of the cell biology of lipid droplets and the biosynthesis of liver lipoproteins and attempts to explain how HCV hijacks these organelles and pathways to assemble its lipo-viro-particles. In particular, this review describes (i) the mechanisms of viral protein translocation to and from the lipid droplet surface and the orchestration of an interface between replication and assembly complexes, (ii) the importance of the triglyceride mobilization from the lipid droplets for HCV assembly, (iii) the interplay between HCV and the lipoprotein synthesis pathway including the role played by apolipoproteins in virion assembly, and finally (iv) the consequences of these complex virus–host interactions on the virion composition and its biophysical properties. The wealth of data accumulated in the past years on the role of the lipid metabolism in HCV assembly and its imprint on the virion properties will guide vaccine design efforts and reinforce our understanding of the hepatic lipid metabolism in health and disease.
Highlights
Mix oil and water, let it stand, and the mixture segregates into two phases; a light oil fraction overlaying the heavier water
As for the liver, with all its metabolic functions, it comprises a specialized machinery for the production and secretion of lipoproteins, which serve to transport various lipid species via the bloodstream to distant sites and tissues in the organism: triglycerides from the lipid droplets are hydrolyzed into fatty acids and re-esterified within the endoplasmic reticulum (ER) in triacylglycerides (TAGs) that are packaged into very-low-density lipoproteins (VLDLs)
This laborious endeavor taught the following lessons: (i) hepatitis C virus (HCV) virion is heterogenous in size, in a range from 40 to 140 nm [16,17], roughly in line with filtration and sedimentation velocity gradient experiments [9,18], (ii) comparable to serum lipoproteins, this size is dramatically reduced after delipidation [14,17]; (iii) HCV has no apparent symmetry, neither for its envelope nor for its capsid [14,15,16,17], this is in contrast to the well-arranged flavivirus relatives [9]; (iv) HCV displays its envelope glycoproteins at its surface and a range of apolipoproteins [14,15,16,17]
Summary
Let it stand, and the mixture segregates into two phases; a light oil fraction overlaying the heavier water. “oily” neutral lipids serve as the main energy source. As for the liver, with all its metabolic functions, it comprises a specialized machinery for the production and secretion of lipoproteins, which serve to transport various lipid species via the bloodstream to distant sites and tissues in the organism: triglycerides from the lipid droplets are hydrolyzed into fatty acids and re-esterified within the endoplasmic reticulum (ER) in triacylglycerides (TAGs) that are packaged into very-low-density lipoproteins (VLDLs). HCV has established an intricate network of molecular interactions with its host cell that sustains all steps of its replication cycle. By hijacking the lipid droplets, HCV gets access to the VLDL biogenesis and uses part of this pathway for its morphogenesis This review summarizes these peculiar host-virus interactions and their impact on the virion biophysical properties
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