Abstract
Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Similar to current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients, improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle. In this study, we tested the potential of a cyclophilin inhibitor, CRV431, to affect HBV replication in transgenic mice. We found that oral treatment with CRV431 (50 mg/kg/day) for a period of 16 days significantly reduced liver HBV DNA levels and moderately decreased serum HBsAg levels. We observed an additive inhibitory effect on liver HBV DNA levels in mice treated with a combination of low doses of CRV431 (10 mg/kg/day) and the nucleotide prodrug, tenofovir exalidex (TXL), (5 mg/kg/day). No toxicity was observed in CRV431-treated mice. Although it is well known that CRV431 neutralizes the peptidyl-prolyl isomerase activity of cyclophilins, its anti-HBV mechanism(s) of action remains unknown. Nevertheless, this study provides the first demonstration of a beneficial effect of a cyclophilin inhibitor in vivo in an HBV transgenic mouse model. Altogether our data reveal the potential of CRV431 to be part of improved new therapies for HBV patients.
Highlights
Hepatitis B virus (HBV) infection is a major health burden worldwide with approximately 240 million chronically infected individuals [1,2]
In mice that were codosed with low doses of CRV431 (10 mg/kg/day) and tenofovir exalidex (TXL) (5 mg/kg/day), liver HBV DNA decreased by 80% compared to the vehicle group
The HBV DNA replication forms that decline in the liver upon treatment are likely encapsidated single-stranded DNA (SS) and relaxed circular form (RC) forms that would not be a source of HBsAg mRNA expression
Summary
Hepatitis B virus (HBV) infection is a major health burden worldwide with approximately 240 million chronically infected individuals [1,2]. Chronic HBV infection increases the risk of developing liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma [3,4,5]. Current therapies include interferons (IFN)s and nucleos(t)ide analogs [6,7,8]. IFN alpha and pegylated IFN alpha (PegIFN alpha) enhance the host immune response and block HBV replication.
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