A genetically humanized mouse model for hepatitis C virus infection.
A genetically humanized mouse model for hepatitis C virus infection.
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DOI：
10.1038/nature10168
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发表时间：
2011-06-08
期刊：
影响因子：
64.8
通讯作者：
Ploss, Alexander
中科院分区：
文献类型：
--
作者：
Dorner, Marcus;Horwitz, Joshua A.;Robbins, Justin B.;Barry, Walter T.;Feng, Qian;Mu, Kathy;Jones, Christopher T.;Schoggins, John W.;Catanese, Maria Teresa;Burton, Dennis R.;Law, Mansun;Rice, Charles M.;Ploss, Alexander
丙型肝炎病毒（HCV）仍然是一个主要的医疗问题。抗病毒治疗仅部分有效，并且不存在疫苗。由于缺乏合适的小动物模型，更有效的治疗方法的开发受到阻碍。虽然用人肝细胞异种移植免疫缺陷小鼠已显示出前景，但这些模型受到重要挑战。基于先前的观察结果，即CD81和闭合蛋白（OCLN）包含使小鼠细胞允许HCV体外进入所需的最小人为因素，我们尝试通过遗传方法进行鼠人源化。在这里，我们表明，两个人类基因的表达是足够的，使HCV感染的完全免疫能力的近交系小鼠。我们建立了一个先例，应用小鼠遗传学解剖病毒进入和验证的作用，SCARB 1的HCV摄取。我们证明，HCV可以被阻断被动免疫，以及显示重组牛痘病毒（rVV）载体诱导体液免疫，并赋予部分保护，对异源的挑战。该系统第一次概括了免疫活性啮齿动物中HCV生命周期的一部分，为研究病毒发病机制和免疫力提供了机会，并为体内测试HCV进入抑制剂提供了有效的平台。
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. While 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 (OCLN) 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 SCARB1 for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as show that a recombinant vaccinia virus (rVV) 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.
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