乙型肝炎病毒基因组的复制触发在不存在B型肝炎表面抗原的t

StephenW

ci Rep. 2016 Apr 28;6:24865. doi: 10.1038/srep24865.
Hepatitis B virus genome replication triggers toll-like receptor 3-dependent interferon responses in the absence of hepatitis B surface antigen.
Real CI1, Lu M2, Liu J2,3, Huang X2, Trippler M1, Hossbach M4,5, Deckert J4,5, Jahn-Hofmann K4,6, Ickenstein LM4,7, John MJ4,8, Gibbert K2, Dittmer U2, Vornlocher HP4,5, Schirmbeck R9, Gerken G1, Schlaak JF1,10, Broering R1.
Author information

    1Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
    2Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.
    3Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
    4Roche Kulmbach GmbH, Kulmbach, Germany.
    5Axolabs GmbH, Kulmbach, Germany.
    6Sanofi-Aventis Deutschland GmbH, Nucleic Acid Therapeutics Frankfurt, Germany.
    7Boehringer Ingelheim Pharma GmbH Biberach, Biberach an der Riß, Germany.
    8Moderna Therapeutics, Cambridge, Massachusetts, USA.
    9Department of Internal Medicine, University Hospital at the University of Ulm, Ulm, Germany.
    10Evangelisches Klinikum Niederrhein gGmbH, Duisburg, Germany.

Abstract

The hepatitis B virus (HBV) has been described as stealth virus subverting immune responses initially upon infection. Impaired toll-like receptor signaling by the HBV surface antigen (HBsAg) attenuates immune responses to facilitate chronic infection. This implies that HBV replication may trigger host innate immune responses in the absence of HBsAg. Here we tested this hypothesis, using highly replicative transgenic mouse models. An HBV replication-dependent expression of antiviral genes was exclusively induced in HBsAg-deficient mice. These interferon responses attributed to toll-like receptor 3 (TLR3)-activated Kupffer and liver sinusoidal endothelial cells and further controlled the HBV genome replication. However, activation of TLR3 with exogenous ligands indicated additional HBs-independent immune evasion events. Our data demonstrate that in the absence of HBsAg, hepatic HBV replication leads to Tlr3-dependent interferon responses in non-parenchymal liver cells. We hypothesize that HBsAg is a major HBV-mediated evasion mechanism controlling endogenous antiviral responses in the liver. Eradication of HBsAg as a therapeutic goal might facilitate the induction of endogenous antiviral immune responses in patients chronically infected with HBV.

StephenW

。科学众议员2016年04月28日; 6：24865。 DOI：10.1038 / srep24865。
乙型肝炎病毒基因组的复制触发在不存在B型肝炎表面抗原的toll样受体3依赖性干扰素应答。
真正CI1，鲁​​M2，刘J2,3，黄X2，特里普勒M1，Hossbach M4,5，Deckert J4,5，雅恩 - 霍夫曼K4,6，Ickenstein LM4,7，约翰MJ4,8，Gibbert K2，U2迪特默， Vornlocher HP4,5，Schirmbeck R9，Gerken G1，Schlaak JF1,10，Broering R1。
作者信息

    胃肠病学和肝病，大学医院在杜伊斯堡 - 埃森大学，德国埃森市教研室。
    病毒学，大学医​​院在杜伊斯堡 - 埃森大学，德国埃森2Institute。
    传染病，协和医院，同济医学院，华中科技大学，武汉，中国的3Department。
    4Roche库姆巴赫有限公司，库姆巴赫，德国。
    5Axolabs有限公司，库姆巴赫，德国。
    6Sanofi - 安万特德国有限公司，核酸治疗德国法兰克福。
    7Boehringer殷格翰制药有限公司比伯拉赫，里斯河畔比伯拉赫，德国。
    8Moderna治疗，剑桥，美国马萨诸塞州。
    内科，大学医院9Department在乌尔姆，德国乌尔姆大学的。
    10Evangelisches KLINIKUM莱茵公益有限责任公司，德国杜伊斯堡。

抽象

乙肝病毒（HBV）已被描述为隐形病毒在感染后最初颠覆免疫应答。由HBV表面抗原（HBsAg）受损toll样受体信号衰减的免疫反应，以促进慢性感染。这意味着HBV复制可能触发在不存在的HBsAg宿主先天免疫反应。在这里，我们测试这个假设，使用高度可复制转基因小鼠模型。抗病毒基因的HBV复制依赖性表达的HBsAg中的缺陷小鼠是专门诱导。归因于toll样受体3（TLR3）这些干扰素的反应活化的库普弗和肝窦内皮细胞，并进一步控制的HBV基因组的复制。然而，用外源性配体的TLR3的活化表明附加HBs抗体无关的免疫逃避的事件。我们的数据表明，在不存在的HBsAg，肝HBV复制导致非实质肝细胞TLR3依赖性干扰素应答。我们推测，乙肝表面抗原是一个重大的HBV介导的规避​​机制控制在肝脏内源性抗病毒反应。的HBsAg根除作为治疗目标可能促进内源性抗病毒免疫应答的慢性感染HBV的患者的诱导。