Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.

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.

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