Date Published: June 10, 2019
Publisher: Public Library of Science
Author(s): Philippe Gallay, Daren Ure, Michael Bobardt, Udayan Chatterji, James Ou, Daniel Trepanier, Robert Foster, Haitao Guo.
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.
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 [3–5]. Current therapies include interferons (IFN)s and nucleos(t)ide analogs [6–8]. IFN alpha and pegylated IFN alpha (PegIFN alpha) enhance the host immune response and block HBV replication. The nucleos(t)ide analogs adefovir, entecavir, lamivudine, telbivudine and tenofovir prevent HBV reverse transcription and replication, leading to a beneficial impact on the development of viral pathogenesis. Nevertheless, nucleos(t)ide analogs fail to completely eradicate HBV from infected cells due to the resiliency of the HBV genome, which forms a stable minichromosome—the covalently closed circular DNA (cccDNA)—in the nucleus of hepatocytes. A cure for HBV will likely require the elimination of cccDNA from infected hepatocytes. Reminiscent of current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients [9,10], improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle.
HBV transgenic mice contain a complete viral genome integrated into the chromosomes that is constitutively transcribed at high levels in hepatic and renal cells . HBV transgenic mice were pre-screened for serum levels of HBV DNA (Fig 1A), HBsAg (Fig 1B) and HBeAg (Fig 1C) levels to select high-expressers (S1 Table), and block-randomized into groups of 8 mice. Mice were treated daily for a period of 16 days with i) vehicle; ii) 10 mg/kg of CRV431; iii) 50 mg/kg of CRV431; iv) 5 mg/kg of TXL; v) 10 mg/kg of TXL; and a combination of 10 mg/kg of CRV431 and 5 mg/kg of TXL.
Current therapies for HBV treatment include interferons (IFN)s and nucleos(t)ide analogs. IFN treatments are associated with side-effects, and antiviral treatments do not lead to the elimination of the virus due to the persistence of cccDNA in HBV-infected hepatocytes. Therefore, there is a critical need for the development of improved therapies for HBV patients.