title: Activation of anti-hepatitis C virus responses via Toll-like receptor 7.
abstract: IFN-alpha is used to suppress the replication of hepatitis C virus (HCV) in chronically infected patients with partial success. Here we present evidence showing that a ligand of Toll-like receptor 7 (TLR7) can induce anti-HCV immunity not only by IFN induction, but also through an IFN-independent mechanism. Human hepatocyte line Huh-7 carrying an HCV replicon expressed TLR7, and activation of the receptor induced several antiviral genes including IFN regulatory factor-7. Inhibitors of the enzyme inosine monophosphate dehydrogenase augmented both IFN-dependent and -independent antiviral effect. Prolonged exposure of Huh-7 cells to a TLR7 ligand [SM360320 (9-benzyl-8-hydroxy-2-(2-methoxyethoxy)adenine)], alone or in combination with an inosine monophosphate dehydrogenase inhibitor, reduced HCV levels dose dependently. Immunohistochemical analysis of livers shows that TLR7 is expressed in hepatocytes of normal or HCV-infected people. Because TLR7 agonists can impede HCV infection both via type I IFN and independently of IFN, they may be considered as an alternative treatment of chronic HCV infection, especially in IFN-alpha-resistant patients.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0663, USA.
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Christina C N
authors.initials: CC
authors.lastname: Wu
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.forename: Kyoko
authors.initials: K
authors.lastname: Katakura
authors.forename: Yu-Tsueng
authors.initials: YT
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.forename: Rommel
authors.initials: R
authors.lastname: Tawatao
authors.forename: Michelle
authors.initials: M
authors.lastname: Chung
authors.forename: Carol
authors.initials: C
authors.lastname: Shen
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D008562:Membrane Glycoproteins; C508876:SM360320; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D000225:Adenine