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CANNABINOIDS BLOCK INTERFERON-MEDIATED
SUPPRESSION OF HEPATITIS C VIRUS (HCV) REPLICATION
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Reported by Jules Levin
http://www.natap.org
from AASLD
Nov 11, 2005, San Francisco
Seela Ramesh, Faridodin Mirshahi, Jayanta Choudhury, Arun Sanyal, Virginia Commonwealth University, Richmond, VA
Background: Many patients with HCV infection use cannabinoids. Cannabinoid receptor activation has both direct effects on hepatocytes and T-cell function. These could affect the virologic response to HCV treatment. The potential effects of cannabinoids on interferon-mediated suppression of viral replication were not
known.
Specific Aims: To define the effects of tetrahydrocannabinol (THC) and methanandamide (MA) a CB receptor agonist on interferonmediated
suppression of HCV replication in hepatocytes.
Methods: HCV virus replication was measured by negative strand quantitative PCR in a commercially available HCV replicon system (APATH). The effects of increasing doses of MA (0-3 uM) and THC (0-1.5 uM) on HCV replication was first measured.
Next, the effect of MA and THC on a-interferon mediated suppression of HCV replication was measured. The specificity of these effects
were tested by pharmacologic blockade of CB1 and CB2 receptors.
Next, the effects of MA on interferon-mediated increased on protein kinase R (PKR) and interferon response factor (IRF) mRNA (measured by qPCR), and protein (measured by Western blot) were measured.
Results: Compared to controls, MA and THC produced a 40-62% decrease in HCV replication. These effects were most marked after 12 hours of exposure. As expected, IFN (5000 IU/ml) produced a 90% inhibition of HCV replication.
MA as well as THC blocked the IFN-mediated inhibition of HCV replication. These effects could be blocked by the CB1 receptor antagonist SR 141716
but not by a CB2 antagonist SR144528. MA and THC also blocked the interferon-mediated increase in PKR and IRF mRNA and protein.
Conclusions: THC and other CB1 receptor agonists can block the IFN-mediated suppression of HCV replication in a replicon system by inhibiting IFN-induction of IRF and PKR. The clinical relevance of these data should be assessed by correlation of cannabinoid use with virologic response to IFN therapy.
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