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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination
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The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination

机译：I型清道夫受体的后结合活性介导了丙型肝炎病毒感染和病毒传播的启动

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摘要

Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. Conclusion: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI.
机译：B类清道夫受体（SR-BI）是在肝脏中高表达并调节HDL代谢的高密度脂蛋白（HDL）受体。丙型肝炎病毒（HCV）能够与SR-BI直接相互作用，并要求该受体有效进入肝细胞以建立生产性感染。据报道，在此过程中，脂蛋白，SR-BI和HCV包膜糖蛋白之间发生了复杂的相互作用。已证明SR-BI在HCV进入的结合和结合后步骤中起作用。尽管参与HCV结合的SR-BI决定因素已得到部分表征，但SR-BI的后结合功能仍然未知。为了揭示SR-BI在病毒启动和传播中的机制作用，我们生成了一类新的抗SR-BI单克隆抗体，它们在HCV进入过程中干扰后结合步骤，而不会干扰HCV颗粒与靶细胞表面的结合。使用表达鼠类和人SR-BI的新型抗体和细胞系，我们证明SR-BI的后结合功能对于HCV感染的起始和病毒的传播均具有关键影响。有趣的是，SR-BI的这种后结合功能似乎与HDL相互作用无关，但直接与其脂质传递功能有关。结论：综上所述，我们的结果揭示了SR-BI后结合功能在不需要受体-E2 / HDL相互作用的病毒HCV感染的起始和维持中的关键作用。 SR-BI介导的HCV进入的分子机制的解剖为特异性抑制SR-BI的前病毒功能的进入抑制剂的设计开辟了新的视角。

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