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Original article
Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene
  1. Tsunamasa Watanabe1,
  2. Fuminaka Sugauchi2,
  3. Yasuhito Tanaka1,
  4. Kentaro Matsuura3,
  5. Hiroshi Yatsuhashi4,
  6. Shuko Murakami1,
  7. Sayuki Iijima1,
  8. Etsuko Iio3,
  9. Masaya Sugiyama5,
  10. Takashi Shimada6,
  11. Masakazu Kakuni6,
  12. Michinori Kohara7,
  13. Masashi Mizokami5
  1. 1Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  2. 2Department of Gastroenterology, Nagoya City Koseiin Medical Welfare Center, Nagoya, Japan
  3. 3Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  4. 4Department of Therapeutic Research, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
  5. 5The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
  6. 6PhoenixBio Co. Ltd., Higashi-Hiroshima, Japan
  7. 7Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
  1. Correspondence to Dr Masashi Mizokami, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine 1–7–1, Kohnodai, Ichikawa 272–8516, Japan; mmizokami{at}hospk.ncgm.go.jp

Abstract

Objective Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment.

Design Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks.

Results There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes.

Conclusions As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.

  • HCV
  • Antiviral Therapy
  • Genetic Polymorphisms
  • Interferon
  • Liver Immunology

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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