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Two Methods of Heterokaryon Formation to Discover HCV Restriction Factors
Published on: July 16, 2012
Analysis of Hepatitis C Virus Particle Heterogeneity in Immunodeficient Human Liver Chimeric fah-/- Mice
Ursula Andreo1, Ype P de Jong1,2, Margaret A Scull1
1Center for the Study of Hepatitis C, The Rockefeller University, New York, New York.
Insights
Hepatitis C virus (HCV) particle density and infectivity change over time in a mouse model. A high-sucrose diet alters HCV particle characteristics, influencing infectivity and density.
Area of Science:
- Virology
- Hepatology
- Immunology
Background:
- Hepatitis C virus (HCV) causes chronic liver disease and is a primary reason for liver transplants.
- HCV particles exhibit varied densities in blood, linked to lipoproteins, but in vitro infectivity is limited.
- Better in vivo models are needed to study HCV particle characteristics.
Purpose of the Study:
- To investigate how the buoyant density of infectious Hepatitis C virus (HCV) particles changes over time in vivo.
- To assess the impact of a high-sucrose diet on HCV particle density and infectivity.
Main Methods:
- Infection of immunodeficient human liver chimeric mice with J6/JFH1 HCV.
- Ultracentrifugation of mouse serum on iodixanol gradients to fractionate viral particles.
- Evaluation of a high-sucrose diet's effect on lipoproteins and HCV particle properties.
Main Results:
- Early in infection, higher infectivity was observed in lower-density HCV fractions.
- Viral particle heterogeneity increased, and overall in vitro infectivity decreased during infection.
- A high-sucrose diet caused a slight shift in HCV infectivity to lower densities, altering lipid distribution.
Conclusions:
- HCV particle buoyant density heterogeneity evolves during infection.
- Diet, specifically a high-sucrose diet, can influence HCV particle characteristics and infectivity.
Background & Aims:
Hepatitis C virus (HCV) is a leading cause of chronic liver diseases and the most common indication for liver transplantation in the United States. HCV particles in the blood of infected patients are characterized by heterogeneous buoyant densities, likely owing to HCV association with lipoproteins. However, clinical isolates are not infectious in vitro and the relative infectivity of the particles with respect to their buoyant density therefore cannot be determined, pointing to the need for better in vivo model systems.
Methods:
To analyze the evolution of the buoyant density of in vivo-derived infectious HCV particles over time, we infected immunodeficient human liver chimeric fumaryl acetoacetate hydrolase-/- mice with J6/JFH1 and performed ultracentrifugation of infectious mouse sera on isopicnic iodixanol gradients. We also evaluated the impact of a high sucrose diet, which has been shown to increase very-low-density lipoprotein secretion by the liver in rodents, on lipoprotein and HCV particle characteristics.
Results:
Similar to the severe combined immunodeficiency disease/Albumin-urokinase plasminogen activator human liver chimeric mouse model, density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions early after infection. However, over the course of the infection, viral particle heterogeneity increased and the overall in vitro infectivity diminished without loss of the human liver graft over time. In mice provided with a sucrose-rich diet we observed a minor shift in HCV infectivity toward lower density that correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Conclusions:
Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet.
