Different anti-HCV profiles of statins and their potential for combination therapy with interferon

Abstract

We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A ( P ersistent hepatitis C virus (HCV) infection causes liver fibrosis and hepatocellular carcinoma. Approximately 170 million people worldwide are infected with HCV. The combination of pegylated interferon (IFN) with ribavirin is the current standard therapy for chronic hepatitis C (CHC) and yields a sustained virological response (SVR) rate of about 55%. 1 This means that about 45% of patients with CH C are still threatened by the progression of the disease to cirrhosis and hepatocellular carcinoma. Until 1999, when Lohmann et al. developed the subgenomic replicon of HCV, it was difficult to screen anti-HCV reagents. 2 Many improvements followed that breakthrough, such as a genome-length HCV RNA replication system 3,4 and a subgenomic replicon with a reporter assay system 5 ; more recently, Wakita et al. used a genotype 2a strain, JFH1, to produce the infectious virus in cell culture. [6][7][8] Genotype 1 is the major genotype of HCV found in Japan, the United States, and many other countries. Unfortunately, the SVR rate after combination therapy of pegylated IFN with ribavirin is less than 50% for this genotype. To find a more effective therapy especially for CHC patients with genotype 1, we recently developed a genome-length HCV RNA (strain O of genotype 1b) replication reporter system (OR6), which has been an effective screening tool. 9,10 Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are in wide use for the treatment of hypercholesterolemia. Recently, it

The mevalonate pathway regulates microRNA activity in Caenorhabditis elegans

“…The mammalian cardiac miRNA miR-208 has been implicated in cardiac fibrosis: Deletion of miR-208 suppresses the high-blood-pressure induction of fibrosis by the heterochronic misexpression of the fetal myosin heavy-chain gene (32). Moreover, the mammalian miRNA miR-122 activates the replication of the hepatitis C virus (HCV) via complementary sequences in the 5′ UTR of the virus (33)(34)(35)(36). Statins emerged from drug screens for inhibition of HCV replication and act via blocking the geranylgeranyl pyrophosphate output of the mevalonate pathway (37,38), which possibly mediates the membrane localization of a particular viral replication protein or downregulates mir-122 function in a manner similar to the inhibition of let-7 and lin-4 miRNA function in C. elegans we have found.…”

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

“…However, cell culture models of HCV infection have demonstrated that anti-HCV activity is not the same for all statins: fluvastatin, atorvastatin, simvastatin, and lovastatin inhibit viral replication to variable extents, whereas pravastatin and rosuvastatin have little to no anti-HCV activity. [18][19][20][21] The underlying mechanism remains unclear; however, data suggest that HCV enters hepatocytes via several lipoprotein receptors (LDL and scavenger receptor class B type 1). At first glance, this appears to be counterintuitive because the statins increase LDL receptors on hepatocytes and in theory increase HCV infectivity.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…Antiviral effects of statins have also been described for HBV, HIV, influenza virus, DENV, HCMV and norovirus [161][162][163][164][165][166][167][168][169] . However the antiviral efficacy of statins in vivo was only marginal and drug-drug interactions with DAAs have been reported 170,171 . While this terminated further use of statins as antiviral drugs, the data taken together underline the important role of the host´s lipid metabolism in viral replication 78 .…”