Rapid reversal of innate immune dysregulation in blood of patients and livers of humanized mice with HCV following DAA therapy

PLoS One. 2017 Oct 17;12(10):e0186213. doi: 10.1371/journal.pone.0186213. eCollection 2017.

Abstract

Results: First, in patients receiving two different combinations of DAAs, we found that DAAs induced not only rapid viral clearance, but also a re-setting of antiviral immune responses in the peripheral blood. Specifically, we see a rapid decline in the expression of genes associated with chronic IFN stimulation (IFIT3, USP18, IFIT1) as well as a rapid decline in genes associated with inflammation (IL1β, CXCL10, CXCL11) in the peripheral blood that precedes the complete removal of virus from the blood. Interestingly, this rapid reversal of innate immune activation was not seen in patients who successfully clear chronic HCV infection using IFN-based therapy. Next, using a novel humanized mouse model (Fah-/-RAG2-/-IL2rgnull-FRG), we assessed the changes that occur in the hepatic tissue following DAA treatment. DAA-mediated rapid HCV clearance resulted in blunting of the expression of proinflammatory responses while functionally restoring the RIG-I/MAVS axis in the liver of humanized mice.

Conclusions: Collectively, our data demonstrate that the rapid viral clearance following treatment with DAAs results in the rebalancing of innate antiviral response in both the peripheral blood and the liver as well as enhanced antiviral signaling within previously infected hepatocytes.

MeSH terms

  • Aged
  • Animals
  • Antiviral Agents / administration & dosage
  • Benzazepines / administration & dosage
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Hepacivirus / drug effects
  • Hepacivirus / genetics*
  • Hepacivirus / pathogenicity
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / virology
  • Hepatocytes / drug effects
  • Hepatocytes / virology
  • Humans
  • Imidazoles / administration & dosage
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics*
  • Indoles / administration & dosage
  • Inflammation / drug therapy
  • Inflammation / genetics*
  • Inflammation / virology
  • Isoquinolines / administration & dosage
  • Liver / drug effects
  • Liver / virology
  • Male
  • Mice
  • Middle Aged
  • Sulfonamides / administration & dosage

Substances

  • 8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide
  • Antiviral Agents
  • Benzazepines
  • Imidazoles
  • Indoles
  • Isoquinolines
  • Sulfonamides
  • daclatasvir
  • asunaprevir