A chimeric GB virus B with 5′ nontranslated RNA sequence from hepatitis C virus causes hepatitis in tamarins
A chimeric GB virus B with 5′ nontranslated RNA sequence from hepatitis C virus causes hepatitis in tamarins
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DOI：
10.1002/hep.20656
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发表时间：
2005-05-01
期刊：
影响因子：
13.5
通讯作者：
Martin, A
中科院分区：
文献类型：
--
作者：
Rijnbrand, R;Yang, Y;Martin, A
只有人类和黑猩猩是完全允许复制丙型肝炎病毒（HCV）的，丙型肝炎病毒是世界范围内肝硬化和癌症的重要原因。缺乏合适的动物模型限制了对候选丙型肝炎治疗药物进行体内评估的机会，并减缓了该领域的进展。在这里，我们描述了一种来自GB病毒B （GBV-B）的嵌合病毒，GBV-B是黄病毒科的一种未分类的嗜肝病毒，与HCV密切相关，感染绢毛猴（Saguinus sp.），其中一个功能重要的HCV调节序列取代了GBV-B基因组5‘非翻译区（5’ ntr）的类似序列。移植序列包含内部核糖体进入位点（IRES）的结构域III，它直接结合40S核糖体亚基，是候选治疗药物的靶标。嵌合的5'NTR保留了核糖体结合活性，在无细胞翻译反应和转染的原代绒猴肝细胞培养中都能指导蛋白质翻译。从嵌合RNA中救出的病毒在柽柳猴的肝脏中复制，引起典型的病毒性肝炎的生化和组织病理学变化。然而，适应性突变需要在基因组的其他地方进行有效的复制。病毒不能从交换IRES结构域II的其他具有翻译能力的嵌合rna中获救。因此，5'NTR似乎包含与病毒基因组内其他位点或病毒蛋白相互作用的病毒特异性复制信号。总之，这种新型嵌合黄病毒为HCV复制机制提供了新的见解，同时可能促进体内候选治疗方法的评估。
Only humans and chimpanzees are fully permissive for replication of hepatitis C virus (HCV), an important cause of liver cirrhosis and cancer worldwide. The absence of suitable animal models limits opportunities for in vivo evaluation of candidate hepatitis C therapeutics and slows progress in the field. Here, we describe a chimeric virus derived from GB virus B (GBV-B), an unclassified hepatotropic member of the family Flaviviridae that is closely related to HCV and infects tamarins (Saguinus sp.), in which a functionally important HCV regulatory sequence replaced an analogous sequence in the 5' nontranslated region (5'NTR) of the GBV-B genome. The transplanted sequence comprised domain III of the internal ribosome entry site (IRES), which directly binds the 40S ribosome subunit and is a target for candidate therapeutics. The chimeric 5'NTR retained ribosome binding activity and was competent in directing protein translation both in cell-free translation reactions and in transfected primary tamarin hepatocyte cultures. Virus rescued from the chimeric RNA replicated in the liver of tamarins, causing biochemical and histopathological changes typical of viral hepatitis. However, adaptive mutations were required elsewhere in the genome for efficient replication. Virus was not rescued from other, translationally competent, chimeric RNAs in which domain II of the IRES was exchanged. Thus, the 5'NTR appears to contain virus-specific replication signals that interact with other sites within the viral genome or with viral proteins. In conclusion, such novel chimeric flaviviruses offer opportunities for new insights into HCV replication mechanisms, while potentially facilitating the evaluation of candidate therapeutics in vivo.