The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity, and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus from wild rats (Rattus norvegicus), RHV‐rn1; acquired the complete viral genome sequence; and developed an infectious reverse genetics system. RHV‐rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5′ and 3′ untranslated regions. We used site‐directed and random mutagenesis to determine that only the first of the two microRNA‐122 seed sites in the viral 5′ untranslated region is required for viral replication and persistence in rats. Next, we used the clone‐derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV‐rn1 possesses several HCV‐defining hallmarks: hepatotropism, propensity to persist, and the ability to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV‐rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct‐acting antiviral therapy, sofosbuvir, effectively suppresses chronic RHV‐rn1 infection in rats. Conclusion: We developed RHV‐rn1‐infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV‐related viral persistence, immunity, and pathogenesis. (Hepatology 2018).

中文翻译：

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丙型肝炎样病毒大鼠模型中的病毒持续性、肝脏疾病和宿主反应

丙型肝炎病毒 (HCV) 缺乏相关的、易处理的和免疫活性的动物模型，严重阻碍了对病毒持久性、免疫和发病机制的研究。在缺乏具有强大 HCV 感染的免疫活性模型的情况下，其天然宿主中的同源肝炎病毒可能会提供有用的替代模型。我们从野生大鼠（Rattus norvegicus）中分离出一种啮齿类肝炎病毒，RHV-rn1；获得完整的病毒基因组序列；并开发了一种传染性反向遗传学系统。RHV-rn1 在基因组特征上类似于 HCV，包括多蛋白切割位点的模式和病毒 5' 和 3' 非翻译区的二级结构。我们使用定点和随机诱变来确定病毒 5' 非翻译区中的两个 microRNA-122 种子位点中的第一个是病毒复制和在大鼠中持续存在所必需的。接下来，我们使用克隆衍生的病毒后代感染了几种近交和远交大鼠品系。我们的结果确定 RHV-rn1 具有几个定义 HCV 的标志：嗜肝性、持续性倾向和诱导逐渐肝损伤的能力。肝脏样本的组织学检查显示慢性感染大鼠存在淋巴聚集物、实质炎症以及大泡和微泡脂肪变性。基因表达分析表明，大鼠 RHV-rn1 感染期间的肝内反应反映了 HCV 感染的反应，包括干扰素信号通路的持续激活。最后，我们确定 HCV 直接作用抗病毒疗法的主干药物索非布韦有效抑制大鼠慢性 RHV-rn1 感染。结论：我们开发了 RHV-rn1 感染大鼠作为完全免疫活性和信息丰富的替代模型，以描绘 HCV 相关病毒持续存在、免疫和发病机制的机制。（肝病学 2018）。