2014 Jul 22. pii: vir.0.067231-0. doi: 10.1099/vir.0.067231-0. [Epub ahead of print]
Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.
Abstract
Direct acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed. Lipid metabolism is closely linked with hepatitis C virus (HCV) replication and endocannabinoids are major regulators of lipid homeostasis. The cannabinoid 1 (CB1) receptor mediates these effects in the liver. We have previously shown up-regulation of CB1 receptors in the livers of patients with CHC, and in a HCV cell culture model. Here we investigated whether CB1 blockade inhibits HCV replication. The antiviral effect of a CB1 antagonist, AM251 was examined in the JFH1 cell culture and subgenomic replicon models. The effects on the expression of genes involved in lipid metabolism were also measured. CB1 shRNA was used to confirm that the effects were specific for the cannabinoid receptor. Treatment with AM251 strongly inhibited HCV RNA (~70%), viral protein (~80%), the production of new virus particles (~70%), and virus infectivity (~90%). As expected, AM251 reduced the expression of pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by AMPK. Stable CB1 knockdown of cells infected with HCV showed reduced levels of HCV RNA, compared with controls. Reduced CB1 signalling inhibits HCV replication using either pharmacological inhibitors or CB1 shRNA. This may be due, at least in part, to reduced lipogenesis, mediated by AMPK activation. We suggest that CB1 antagonists may represent an entirely new class of drugs with activity against HCV.
Copyright © 2014, the Society for General Microbiology.
Copyright © 2014, the Society for General Microbiology.
KEYWORDS:
AM251; AMPK; CB1 antagonits; Hepatitis C virus; cannabinoid 1 receptor
- PMID:
- 25053565
- [PubMed – as supplied by publisher]
