title: Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response.
abstract: Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype.
  
  
  CONCLUSIONS
  Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.forename: Antonios
authors.initials: A
authors.lastname: Katsounas
authors.forename: Richard
authors.initials: R
authors.lastname: Lempicki
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Bhavana
authors.initials: B
authors.lastname: Shivakumar
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000418:Albumins / Q000008:administration & dosage / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D060085:Coinfection / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000276:immunology*; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000095022:Interferon Lambda
chemical_list: D000418:Albumins; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C531108:albinterferon alfa-2b; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a