Completion of the entire hepatitis C virus life cycle in genetically humanized mice.
Completion of the entire hepatitis C virus life cycle in genetically humanized mice.
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作者：
全世界有超过1.3亿人慢性感染丙型肝炎病毒（HCV），有发展为严重肝病的风险。抗病毒治疗仅部分有效，并且没有疫苗。由于缺乏小动物模型，更有效的治疗方法的开发受到阻碍。基于CD 81和occludin（OCLN）包含使小鼠细胞允许HCV进入所需的最小人类因子集的观察，我们先前表明这两种人类基因的瞬时表达足以使病毒摄取到完全免疫活性的近交系小鼠中。在这里，我们证明了稳定表达人CD 81和OCLN的转基因小鼠也支持HCV进入，但先天性和适应性免疫反应限制了体内HCV感染。在感染HCV的基因人源化小鼠中，抗病毒免疫减弱导致数周内可测量的病毒血症。在缺乏必需的细胞辅因子亲环素A（CypA）的小鼠中，HCV RNA复制显着减少，提供了遗传证据表明该过程被忠实地重演。使用由NS 3 -4A蛋白酶激活的基于细胞的荧光报告，我们在体内观察单个肝细胞中的HCV感染。持续感染的小鼠产生新的感染性颗粒，其可以用直接作用的抗病毒药物治疗来抑制，从而首次提供了在近交系小鼠中完成整个HCV生命周期的证据。这种基因人源化小鼠模型为体内基因解剖HCV感染开辟了新的机会，并为测试和优先考虑候选药物和疫苗提供了重要的临床前平台。
More than 130 million people world-wide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice. Here, we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viremia over several weeks. In mice lacking the essential cellular co-factor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes in vivo. Persistently infected mice produce de novo infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing for the first time evidence for the completion of the entire HCV life-cycle in inbred mice. This genetically humanized mouse model opens new opportunities to genetically dissect HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug and vaccine candidates.
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影响因子：
64.8
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
通讯作者：
Ploss, Alexander
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
5.4
作者：
Lin, Liang-Tzung;Noyce, Ryan S.;Richardson, Christopher D.
通讯作者：
Richardson, Christopher D.
影响因子：
56.9
作者：
MULLER, U;STEINHOFF, U;AGUET, M
通讯作者：
AGUET, M
DOI：
10.1073/pnas.0504877103
发表时间：
2006-05-09
影响因子：
11.1
作者：
Pietschmann, Thomas;Kaul, Artur;Bartenschlager, Ralf
通讯作者：
Bartenschlager, Ralf