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Dysregulation of interferon regulatory factors impairs the expression of immunostimulatory molecules in hepatitis C virus genotype 1-infected hepatocytes
  1. Esther Larrea1,
  2. Jose-I Riezu-Boj1,
  3. Rafael Aldabe1,
  4. Laura Guembe2,
  5. Itziar Echeverria1,
  6. Anangi Balasiddaiah1,
  7. Pablo Gastaminza3,
  8. María Pilar Civeira4,5,
  9. Pablo Sarobe1,
  10. Jesus Prieto1,4,5
  1. 1Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), Pamplona, Spain
  2. 2Department of Morphology, Center for Applied Medical Research (CIMA), Pamplona, Spain
  3. 3Department of Cell and Molecular Biology, Centro Nacional de Biotecnologia-CSIC, Madrid, Spain
  4. 4University Clinic of Navarra, University of Navarra, Pamplona, Spain
  5. 5CIBERehd, University of Navarra, Pamplona, Spain
  1. Correspondence to Professor Jesus Prieto or Dr Esther Larrea, Department of Gene Therapy and Hepatology Area, Center for Applied Medical Research, University Clinic of Navarra, University of Navarra, Avda Pio XII 55, Pamplona 31008, Spain; jprieto{at}unav.es or elarrea{at}unav.es

Abstract

Background IL-7 and IL-15 are produced by hepatocytes and are critical for the expansion and function of CD8 T cells. IL-15 needs to be presented by IL-15Rα for efficient stimulation of CD8 T cells.

Methods We analysed the hepatic levels of IL-7, IL-15, IL-15Rα and interferon regulatory factors (IRF) in patients with chronic hepatitis C (CHC) (78% genotype 1) and the role of IRF1 and IRF2 on IL-7 and IL-15Rα expression in Huh7 cells with or without hepatitis C virus (HCV) replicon.

Results Hepatic expression of both IL-7 and IL-15Rα, but not of IL-15, was reduced in CHC. These patients exhibited decreased hepatic IRF2 messenger RNA levels and diminished IRF2 staining in hepatocyte nuclei. We found that IRF2 controls basal expression of both IL-7 and IL-15Rα in Huh7 cells. IRF2, but not IRF1, is downregulated in cells with HCV genotype 1b replicon and this was accompanied by decreased expression of IL-7 and IL-15Rα, a defect reversed by overexpressing IRF2. Treating Huh7 cells with IFNα plus oncostatin M increased IL-7 and IL-15Rα mRNA more intensely than either cytokine alone. This effect was mediated by strong upregulation of IRF1 triggered by the combined treatment. Induction of IRF1, IL-7 and IL-15Rα by IFNα plus oncostatin M was dampened in replicon cells but the combination was more effective than either cytokine alone.

Conclusions HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15Rα. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.

  • HCV
  • Chronic Viral Hepatitis
  • Gene Expression
  • Immune Response

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