Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells.
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-alpha 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.


CONCLUSIONS
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.
Chang
Serena
S
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
Kodys
Karen
K
Szabo
Gyongyi
G
D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000254:growth & development; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000502:physiology; D016898:Interferon-alpha / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation
C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D012333:RNA, Messenger; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7