Activation of anti-hepatitis C virus responses via Toll-like receptor 7.
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.
Lee
Jongdae
J
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0663, USA.
Wu
Christina C N
CC
Lee
Ki Jeong
KJ
Chuang
Tsung-Hsien
TH
Katakura
Kyoko
K
Liu
Yu-Tsueng
YT
Chan
Michael
M
Tawatao
Rommel
R
Chung
Michelle
M
Shen
Carol
C
Cottam
Howard B
HB
Lai
Michael M C
MM
Raz
Eyal
E
Carson
Dennis A
DA
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
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