From the Journals

Biophysical properties of HCV evolve over course of infection

 

Key clinical point: The biophysical properties of the hepatitis C virus evolve during the course of infection and shift with dietary changes.

Major finding: Density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions soon after infection, but heterogeneity subsequently increased while infectivity decreased. A 5-week diet of 10% sucrose produced a minor shift toward infectivity that correlated with redistribution of triglycerides and cholesterol.

Data source: A study of 13 human liver chimeric mice.

Disclosures: Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.

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Lipid components of HCV particle may be targetable

A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.

Dr. Agata Budkowska
HCV species and tissue specificity is limited to the human hepatocyte. Since hepatoma cells in vitro produce virus particles with incomplete lipoprotein composition, mouse models with transplanted human primary hepatocytes have been developed to investigate infection in vivo.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.

Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.

Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.

Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.

They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.

Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.

The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.

In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.

HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”

Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.