Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune‐mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell‐culture models and humanized Alb‐uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV‐infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high‐level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779–1793)

中文翻译：

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乙型肝炎病毒逃避肝细胞的先天免疫，但激活巨噬细胞产生细胞因子

乙型肝炎病毒 (HBV) 特异性感染肝细胞并引起免疫介导的肝损伤。HBV 如何与感染早期的先天免疫相互作用，无论是与肝细胞还是肝脏中的其他细胞，仍然存在争议。为了解决这个问题，我们利用了各种人类细胞培养模型和人源化的 Alb-uPA/SCID 小鼠。尽管 HBV 复制强劲，但所有这些模型都无法产生干扰素 (IFN) 反应。为了阐明缺乏 IFN 反应的机制，我们检查了 HBV 是否积极抑制肝细胞的先天免疫功能。通过用已知的 IFN 信号通路诱导剂处理 HBV 感染的细胞，我们没有观察到 HBV 感应或下游 IFN 反应的改变。我们发现 DNA 先天传感通路在肝细胞中的活性很差，与 HBV 的先天免疫识别静音一致。暴露于高水平 HBV 后，人巨噬细胞可能被激活，炎症细胞因子表达增加。结论：HBV表现得像一种“隐形”病毒，不会被感染肝细胞的内在先天免疫感知，也不会主动干扰。巨噬细胞能够感知 HBV，但需要暴露于高 HBV 滴度，这可能解释了急性感染期间的长“窗口期”和 HBV 慢性感染的倾向。（肝病学 2017；66：1779–1793）受感染肝细胞的内在先天免疫。巨噬细胞能够感知 HBV，但需要暴露于高 HBV 滴度，这可能解释了急性感染期间的长“窗口期”和 HBV 慢性感染的倾向。（肝病学 2017；66：1779–1793）受感染肝细胞的内在先天免疫。巨噬细胞能够感知 HBV，但需要暴露于高 HBV 滴度，这可能解释了急性感染期间的长“窗口期”和 HBV 慢性感染的倾向。（肝病学 2017；66：1779–1793）