Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.
Nature. 2011 Jun 8;474(7350):208-11. doi: 10.1038/nature10168.
Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.
丙型肝炎病毒 (HCV) 仍然是一个主要的医学问题。抗病毒治疗只有部分有效，而且没有疫苗。由于缺乏合适的小动物模型，开发更有效的治疗方法受到了阻碍。虽然将免疫缺陷小鼠与人肝细胞异种移植显示出了前景，但这些模型存在重要的挑战。基于之前的观察结果，即 CD81 和紧密连接蛋白构成了使鼠细胞对 HCV 体外进入具有易感性的最小人类因素，我们试图通过遗传方法进行小鼠人源化。在这里，我们表明表达两种人类基因足以允许 HCV 感染完全免疫的近交系小鼠。我们为应用小鼠遗传学来剖析病毒进入建立了先例，并验证了清道夫受体 B 类 I 型在 HCV 摄取中的作用。我们证明 HCV 可以通过被动免疫来阻断，并且表明重组痘苗病毒载体诱导体液免疫并对异源攻击提供部分保护。该系统首次在免疫功能正常的啮齿动物中重现了 HCV 生命周期的一部分，为研究病毒发病机制和免疫提供了机会，并构成了在体内测试 HCV 进入抑制剂的有效平台。
