Heterogeneity of Hepatitis C Virus Particles and Their Evolution During Infection

epatitis C virus (HCV) was identified by molecular Hcloning of its RNA genome after conventional methods of virus identification failed. This failure was due to both low levels of HCV particles in the blood of infected patients and particle heterogeneity. HCV is a highly variable virus. In addition to 6 genotypes and more than 60 subtypes, HCV mutants circulate in the blood as millions of quasispecies, many of which are able to escape host immune responses and even direct-acting antiviral (DAA) therapy. HCV heterogeneity is also due to the association of virus particles with lipoproteins. Indeed, a peculiarity of HCV is its interaction with hepatic lipid metabolic pathways at all stages of its life cycle. Viral particles are associated with very low-density (VLDL) and low-density lipoproteins, which play a critical role in HCV cell entry (via lipoprotein receptors); morphogenesis and the release of infectious virus particles depend on VLDL synthesis and export pathways. The HCV virion (lipo-viro particle [LVP]) is composed of nucleocapsid and E1E2 envelope glycoproteins, liver cell–derived triglyceride-rich lipoproteins (TRLs), cholesterol, and several apolipoproteins (ApoE, ApoB-100, ApoCI, ApoCII, ApoCIII). The lipid components of the virus determine its size (40–70 nm), buoyant density, hepatotropism and infectivity, morphogenesis, and maturation of virus particles. Lipoproteins and ApoE facilitate viral escape from neutralizing antibodies. Noninfectious forms of HCV in the blood include nucleocapsid-free lipoprotein-like particles and nonenveloped nucleocapsids. HCV particles in the blood vary in size and in content of lipids and apolipoproteins. The concentration and properties of virus particles depend on the stage of infection (acute or chronic) and fluctuate with postprandial lipemia. Both the lipoprotein composition of virus particles and serum lipid profiles might influence a patient’s susceptibility to infection. HCV displays a species and tissue specificity limited to the human hepatocyte, but the density and infectivity of HCV particles depend on the specific type of cell in which the virus is produced. Huh7 hepatoma cells, used to culture HCV in vitro, have deficient lipoprotein metabolism and produce immature VLDLs. Consequently, culture-derived HCV has a different lipid composition, higher density, and lower infectivity than virus strains produced in chimpanzees or in the humanized mouse models. Serum-derived HCV is difficult to grow in vitro. Thus, development of uPA-SCID mouse model with transplanted human primary hepatocytes enabled production of viruses with the appropriate lipid composition for studies of HCV receptors and evaluation of antivirals. Nevertheless, more