Inhibition of HCV by the serpin antithrombin III
1 Division of Viral Pathogenesis, BIDMC, Boston, MA 02215, USA
2 Harvard Medical School, Boston, MA 02215, USA
3 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Virology Journal 2012, 9:226 doi:10.1186/1743-422X-9-226Published: 2 October 2012
Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection, interferon-α based therapy remains challenging for certain populations, including those with unfavorable IL28B genotypes, psychiatric co-morbidity, HIV co-infection, and decompensated liver disease. We have recently shown that ATIII, a serine protease inhibitor (serpin), has broad antiviral properties.
We now show that ATIII is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations. At a mechanistic level using gene-expression arrays, we found that ATIII treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma, including Jun, Myc and BMP2. Using a protein interactive network analysis we found that changes in gene-expression caused by ATIII were dependent on three nodes previously implicated in HCV disease progression or HCV replication: NFκB, P38 MAPK, and ERK1/2.
Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options.