Haem oxygenase-1 polymorphisms can affect HCV replication and treatment responses with different efficacy in humanized mice

Liver Int. 2017 Aug;37(8):1128-1137. doi: 10.1111/liv.13347. Epub 2017 Jan 25.

Abstract

Background & aims: Enhancement of host anti-oxidant enzymes, such as haemoxygenase-1, may attenuate virus-mediated hepatocyte injury, while the induction of HO-1 by cobalt-protoporphyrin-IX (CoPP) administration, as the application of its haem degradation product biliverdin (BV), was shown to hinder HCV replication in vitro. In addition, (GT)n -repeats length in the polymorphic region of the HO-1 promoter may affect HO-1 expression and responsiveness to infection and disease severity. Aim of this study was to investigate the antiviral and hepatoprotective effects of CoPP-mediated HO-1 induction, alone or in combination with interferon alpha (peg-IFNα), in HCV-infected mice harbouring hepatocytes from donors with different HO-1-promoter polymorphisms.

Methods: Upon establishment of HCV infection, CoPP, BV and peg-IFNα were given alone or in combination. Viraemia changes and intrahepatic human gene expression were determined by qRT-PCR and immunohistochemistry.

Results: CoPP administration increased human HO-1 expression and significantly reduced viraemia, although changes correlated with promoter length (Δ0.5log and Δ2log reduction with medium- and short-polymorphism respectively). Polymorphisms did not influence BV-mediated antiviral effects (Δ1log). Notably, HO-1 induction attenuated basal HCV-driven enhancement of interferon genes and pro-inflammatory cytokines, both in cells with short- or medium-polymorphisms. Moreover, simultaneous administration of CoPP and peg-IFNα reduced viraemia even stronger (median 3log), whereas 1log viraemia reduction was determined in mice receiving peg-IFNα monotherapy.

Conclusions: Although the protective function of HO-1 could be elicited in vivo with both host polymorphisms, the strength of HO-1 induction and suppression of HCV occurred in a polymorphism-dependent manner, indicating that host-genetic determinants may affect disease progression and infection outcome.

Keywords: HCV; HO-1; IFNα; humanized uPA mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Biliverdine / pharmacology
  • Biliverdine / therapeutic use
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Hepacivirus / drug effects
  • Hepacivirus / immunology*
  • Hepatitis C / genetics
  • Hepatitis C / therapy*
  • Hepatitis C / virology
  • Humans
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use
  • Mice
  • Polymorphism, Genetic
  • Transcriptional Activation
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Interferon-alpha
  • Heme Oxygenase-1
  • Biliverdine