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

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-IFN alpha), in HCV-infected mice harbouring hepatocytes from donors with different HO-1-promoter polymorphisms. Methods: Upon establishment of HCV infection, CoPP, BV and peg-IFNa 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 (Delta 0.5log and Delta 2log reduction with medium-and short-polymorphism respectively). Polymorphisms did not influence BV-mediated antiviral effects (Delta 1log). 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-IFN alpha reduced viraemia even stronger (median 3log), whereas 1log viraemia reduction was determined in mice receiving peg-IFN alpha 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.