Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice.
Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice.
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免疫能力强的人源化小鼠的持续丙型肝炎病毒感染和肝脏病理学表现。
作者：
大多数丙型肝炎病毒（HCV）感染发展为慢性感染，其导致脂肪变性、肝硬化和肝细胞癌。然而，理解HCV慢性和发病机制受到其狭窄的宿主范围的阻碍，主要限于人类和黑猩猩。最近尝试感染各种人源化小鼠，但未能实现持续的HCV感染，除非敲除必需的先天免疫反应基因。然而，这种免疫受损的人源化小鼠仍然缺乏HCV感染诱导的肝脏发病机制。在这里，我们报告说，转基因小鼠在ICR背景下窝藏人类CD 81和occludin基因（C/OTg）是允许丙型肝炎病毒感染的慢性率与人类相当。在该小鼠模型中，HCV完成其复制周期，导致感染后持续病毒血症和感染性超过12个月，并伴有预期的纤维化和纤维化进展。有利于HCV复制的宿主因素和先天免疫应答不足可能有助于持续存在。最后，NS 3/4蛋白酶抑制剂telaprevir可有效抑制C/OTg小鼠的从头RNA合成和急性HCV感染。因此，慢性丙型肝炎病毒感染完整的复制周期和肝脏病理表现是重演，第一次，在免疫能力的小鼠。该模型将为研究慢性丙型肝炎的机制和开发更好的治疗方法开辟新的途径。
The majority of hepatitis C virus (HCV) infection develops chronic infection, which causes steatosis, cirrhosis and hepatocellular carcinoma. However, understanding HCV chronicity and pathogenesis is hampered by its narrow host range, mostly restricted to human and chimpanzee. Recent endeavour to infect a variety of humanized mice has not been able to achieve persistent HCV infection unless the essential innate immune responsive genes are knocked out. Nevertheless, such immune-compromised humanized mice still lacked HCV infection-induced hepatopathogenesis. Here we report that transgenic mice in ICR background harboring both human CD81 and occludin genes (C/OTg) are permissive to HCV infection at a chronicity rate comparable to humans. In this mouse model, HCV accomplishes its replication cycle, leading to sustained viremia and infectivity for more than 12 months post infection with expected fibrotic and cirrhotic progression. Host factors favorable for HCV replication, and inadequate innate immune-response may contribute to the persistence. Lastly, NS3/4 protease inhibitor telaprevir can effectively inhibit de novo RNA synthesis and acute HCV infection of C/OTg mice. Thus, chronic HCV infection with complete replication cycle and hepatopathologic manifestations is recapitulated, for the first time, in immune-competent mice. This model will open a new venue to study the mechanisms of chronic hepatitis C and develop better treatments.
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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：
5.4
作者：
Bigger, CB;Guerra, B;Lanford, RE
通讯作者：
Lanford, RE
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
29.4
作者：
Bukh, Jens
通讯作者：
Bukh, Jens
影响因子：
5.4
作者：
Chang, Kyung-Soo;Cai, Zhaohui;Luo, Guangxiang
通讯作者：
Luo, Guangxiang