Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
Hepatology. 2010 Jan;51(1):35-42. doi: 10.1002/hep.23256.
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.
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.
丙型肝炎病毒 (HCV) 干扰干扰素 (IFN) 介导的先天免疫防御。 Toll 样受体 (TLR) 7 激动剂可有效抑制 HCV 感染。我们假设 HCV 感染可能会干扰 TLR7 的表达和/或功能，TLR7 是一种识别单链 RNA 的传感器。与对照的未感染 HCV 的细胞相比，表达 HCV（全长、BB7 亚基因组和 JFH-1 克隆）的肝癌细胞中 TLR7 RNA 和蛋白水平降低。在 HCV 感染患者的肝脏中观察到 TLR7 RNA 减少，证实了这一发现的生物学相关性，与对照组相比。IFN-α 治疗或限制性培养条件下的 HCV 清除恢复了降低的 TLR7 表达。用 RNA 聚合酶抑制剂处理表明，与对照组相比，HCV 复制细胞中的 TLR7 半衰期更短。在 HCV 阳性细胞中观察到 TLR7 下游的 IRF7 核易位基线增加，与对照组相比。用 TLR7 配体 R837 刺激可导致对照细胞中显著的 IRF7 核易位。相比之下，HCV 复制细胞显示出减弱的 TLR7 配体诱导的 IRF7 激活。
由于 RNA 不稳定导致的 TLR7 表达降低与 HCV 复制直接相关，并改变 TLR7 诱导的 IRF7 介导的细胞激活。这些结果表明 TLR7 在 HCV 介导的宿主免疫逃避中起作用。
