title: Intrinsic Viral Factors Are the Dominant Determinants of the Hepatitis C Virus Response to Interferon Alpha Treatment in Chimeric Mice.
abstract: BACKGROUND
  Hepatitis C virus infection is a global health problem. New direct-acting antiviral agents have been recently approved. However, due to their high cost and some genotypes remaining difficult to treat, interferon-based therapy with pegylated interferon and ribavirin likely may remain a component of hepatitis C virus treatment for some patients. Unfortunately, pegylated interferon / ribavirin treatment achieved favorable outcomes in less than 50% of patients. Factors determining the outcome to pegylated interferon/ribavirin include both host and viral factors. It has been a major challenge to separate the host and viral factors in most in vivo systems.
  
  
  OBJECTIVE
  We used two hepatitis C virus strains from patients with different interferon-sensitivities and three hepatocyte donors, each with distinct interleukin 28B and interferon lambda 4 single nucleotide polymorphisms to investigate the contributions of viral and host factors to the response of hepatitis C virus to interferon treatment in chimeric mice.
  
  
  CONCLUSIONS
  We found that viral factors were the dominant factors in determining the interferon treatment outcomes in chimeric mice. Host factors, such as pre-treatment liver interferon-stimulated gene expression and single nucleotide polymorphisms near interleukin 28B and interferon lambda 4 coding regions, were less important determinants of the response to interferon in the chimeric mice than they were in patients. Our results also suggest that a complete immune system as seen in patients may be required for host factors such as single nucleotide polymorphisms near interleukin 28B/interferon lambda 4 and pre-treatment liver interferon-stimulated gene upregulation to have an effect on the interferon response.
authors.affiliation: Department of Medical Microbiology and Immunology, Edmonton, Alberta, Canada.|Li Ka Shing Institute of Virology, Katz Centre for Health Research, Edmonton, Alberta, Canada.
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Medical Microbiology and Immunology, Edmonton, Alberta, Canada.|Li Ka Shing Institute of Virology, Katz Centre for Health Research, Edmonton, Alberta, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kobewka
authors.affiliation: Department of Medical Microbiology and Immunology, Edmonton, Alberta, Canada.|Li Ka Shing Institute of Virology, Katz Centre for Health Research, Edmonton, Alberta, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Addison
authors.affiliation: Department of Medical Microbiology and Immunology, Edmonton, Alberta, Canada.|Li Ka Shing Institute of Virology, Katz Centre for Health Research, Edmonton, Alberta, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Lachance
authors.affiliation: Department of Medical Microbiology and Immunology, Edmonton, Alberta, Canada.|Li Ka Shing Institute of Virology, Katz Centre for Health Research, Edmonton, Alberta, Canada.
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005814:Genes, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D018183:Transplantation Chimera; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human