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Impaired expression and function of toll‐like receptor 7 in hepatitis C virus infection in human hepatoma cells
Author(s) -
Chang Serena,
Kodys Karen,
Szabo Gyongyi
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23256
Subject(s) - tlr7 , hepatitis c virus , biology , virology , toll like receptor , interferon , irf7 , rna , tlr9 , viral replication , immunology , immune system , innate immune system , virus , microbiology and biotechnology , gene expression , gene , biochemistry , dna methylation
Hepatitis C virus (HCV) interferes with interferon (IFN)‐mediated innate immune defenses. Toll‐like receptor (TLR) 7 agonists robustly inhibit HCV infection. We hypothesize that HCV infection may interfere with the expression and/or function of TLR7, a sensor of single‐stranded RNA. We identified reduced TLR7 RNA and protein levels in hepatoma cells expressing HCV (full‐length, BB7‐subgenomic, and JFH‐1 clone) compared with control HCV‐naïve cells. The biological relevance of this finding was confirmed by the observation of decreased TLR7 RNA in livers of HCV‐infected patients compared with controls. HCV clearance, by IFN‐α treatment or restrictive culture conditions, restored the decreased TLR7 expression. Treatment with RNA polymerase inhibitors revealed a shorter TLR7 half‐life in HCV‐replicating cells compared with controls. Downstream of TLR7, an increased baseline IRF7 nuclear translocation was observed in HCV‐positive cells compared with controls. Stimulation with the TLR7 ligand R837 resulted in significant IRF7 nuclear translocation in control cells. In contrast, HCV‐replicating cells showed attenuated TLR7 ligand‐induced IRF7 activation. Conclusion: Reduced TLR7 expression, due to RNA instability, directly correlates with HCV replication and alters TLR7‐induced IRF7‐mediated cell activation. These results suggest a role for TLR7 in HCV‐mediated evasion of host immune surveillance. (H EPATOLOGY 2009.)