Inhibition of HCV by the serpin antithrombin III

Area of Science:

• Virology
• Hepatology
• Immunology

Background:

• Interferon-alfa therapy for chronic hepatitis C virus (HCV) infection presents challenges for specific patient groups.
• These challenging populations include those with unfavorable IL28B genotypes, psychiatric comorbidities, HIV co-infection, and decompensated liver disease.
• Antithrombin III (ATIII), a serine protease inhibitor (serpin), has demonstrated broad antiviral properties.

Purpose of the Study:

• To investigate the antiviral capabilities of ATIII against HCV.
• To elucidate the mechanism of action of ATIII in inhibiting HCV replication.
• To identify host cell pathways modulated by ATIII relevant to HCV pathogenesis.

Main Methods:

• Utilized the OR6 replicon model to assess ATIII's efficacy in inhibiting HCV.
• Employed gene-expression arrays to analyze host cell signaling pathways affected by ATIII treatment.
• Conducted protein interaction network analysis to identify key regulatory nodes influenced by ATIII.

Main Results:

• ATIII demonstrated inhibition of HCV replication in the OR6 replicon model at micromolar concentrations.
• ATIII treatment led to the down-regulation of host cell signal transduction factors, including Jun, Myc, and BMP2, implicated in cirrhosis and hepatocellular carcinoma.
• Gene expression changes induced by ATIII were dependent on NFκB, P38 MAPK, and ERK1/2 signaling pathways, known to be involved in HCV disease progression and replication.

Conclusions:

• ATIII effectively inhibits HCV replication.
• ATIII modulates host cell pathways crucial to HCV pathogenesis.
• ATIII stimulates a novel innate antiviral host defense mechanism distinct from current therapeutic strategies.