Activation of Anti-Hepatitis C Virus Responses via Toll-like Receptor 7

IFN-α 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 mechan...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (6), p.1828-1833
Main Authors: Lee, Jongdae, Wu, Christina C. N., Lee, Ki Jeong, Chuang, Tsung-Hsien, Katakura, Kyoko, Liu, Yu-Tsueng, Chan, Michael, Tawatao, Rommel, Chung, Michelle, Shen, Carol, Cottam, Howard B., Lai, Michael M. C., Raz, Eyal, Carson, Dennis A.
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - pharmacology
Animals
Antibodies
Antiviral Agents - pharmacology
Antivirals
B lymphocytes
Biological Sciences
Cells, Cultured
Cytokines
Enzymes
Female
HEK293 cells
Hepacivirus - immunology
Hepatitis
Hepatitis C
Hepatitis C - immunology
Hepatitis C - pathology
Hepatitis C - virology
Hepatitis C virus
Hepatocytes
Hepatocytes - metabolism
Hepatocytes - pathology
Hepatocytes - virology
Humans
Immunology
Inhibitor drugs
Interferon-gamma - metabolism
Ligands
Liver
Membrane Glycoproteins - immunology
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
Replicon
Toll-Like Receptor 7 - genetics
Toll-Like Receptor 7 - immunology
Toll-Like Receptor 7 - metabolism
Virus Replication
Western blotting
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Summary:IFN-α 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-a~-resistant patients.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510801103