Induction of heme oxygenase 1 by HMG-CoA-Reductase inhibitors interferes with HCV replication

Background and Aims: Heme oxygenase 1 (HO–1) induction or over-expression has been shown to interfere with HCV replication. Induction under experimental conditions is obtained by use of cobalt-protoporphyrin-IX (CoPP), which as a heavy metal compound is not acceptable for patient treatment. We investigated anti-viral as well as HO–1 inducing properties of HMG-CoA reductase inhibitors (statins). Methods: HO–1 induction by fluva-, simva-, atorva-, rosuva- and pravastatin in HCV replicon cell lines was measured by real time RT-PCR and Western Blot. HCV replication was analyzed in LucUbiNeo-ET replicon cells, stably expressing HCV genes NS3 to NS5B in combination with firefly luciferase, by luciferase reporter assay. Components of the HO–1 induction pathway were monitored by RT-PCR and stably knocked down by specific si and shRNA . Results: All statins except pravastatin significantly induced HO–1 and decreased HCV replication without cytotoxic effects on the replicon system. Statins increased HO–1 expression by reducing Bach1 and inducing KLF2 expression. The knock down of KLF2 or HO–1 largely abolished inhibitory effects of statins on HCV replication. Conclusions: Induction of HO–1 could become a useful tool to interfere with HCV replication as soon as potent and save HO–1 inducers are available. Statins act anti-virally by inducing HO–1, underlines by knockdown experiments and the fact that the only non-HO–1 inducing statin, pravastatin, is not able to interfere with HCV replication. On the other hand, HO–1 induction by statins is transient and not strong enough to serve as a mono therapy. Combination with other HO–1 inducing agents will improve anti-viral effects.

KLF2 - heme oxygenase 1 - statins