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

Enhancement of host anti-oxidant enzymes, such as heme oxygenase-1, may attenuate virus-mediated hepatocyte injury, while the induction of HO-1 by cobalt-protoporphyrin-IX (CoPP) administration, as the application of its heme degradation product biliverdin (BV), was shown to hinder HCV replication in vitro. Additionally, (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 harboring 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. Viremia changes and intrahepatic human gene expression were determined by qRT-PCR and immunohistochemistry.

RESULTS: CoPP administration increased human HO-1 expression and significantly reduced viremia, 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 viremia even stronger (median 3log), whereas 1log viremia 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. This article is protected by copyright. All rights reserved.