Abstract
Background & AimsHMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication.MethodsHO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non-infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase-inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue.ResultsAll statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease.ConclusionsStatin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease.
Highlights
About 3% of the world’s population are chronically infected with HCV [1], representing a cause of cirrhosis, steatosis and subsequent development of hepatocellular carcinoma (HCC) [2]
We found that all statins, except PRV, were able to induce heme oxygenase 1 (HO-1) expression and reduce HCV replication
Investigating statin effects on HCV replication we found that fluva- (FLV) (Fig. 1B), simva- (SMV) (Fig. 1C), rosuva- (ROV) (Fig. 1D), and atorvastatin (ATV) (Fig. 1E) reduced HCV replication in the subgenomic replicon system in a dose- and time-dependent manner
Summary
About 3% of the world’s population are chronically infected with HCV [1], representing a cause of cirrhosis, steatosis and subsequent development of hepatocellular carcinoma (HCC) [2]. Clinical studies report that e.g. fluvastatin monotherapy reduced HCV replication [11] and enhanced efficacy of IFN alpha [12], while others could not confirm this observation [13,14] or describe a rapid decrease of the viral load without significant effects on sustained virologic response [15] The reasons for such inconsistent effects of statins on HCV replication are not clear, since the lack of prenylation, defined as the mechanism of anti-viral statin effects so far [16], should be achieved by all statins and there are no reports describing e.g. genetic polymorphisms being associated with hypo-responsiveness towards the cholesterol-lowering capacity of statins. Requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication
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