title: Inhibition of HCV by the serpin antithrombin III.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options.
authors.affiliation: Division of Viral Pathogenesis, BIDMC, Boston, MA 02215, USA. masmal@partners.org
authors.forename: Mohammed
authors.initials: M
authors.lastname: Asmal
authors.forename: Michael
authors.initials: M
authors.lastname: Seaman
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Ralf
authors.initials: R
authors.lastname: Geiben-Lynn
mesh_terms: D000990:Antithrombin III / Q000276:immunology / Q000378:metabolism*; D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D000990:Antithrombin III