Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

中文翻译：

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通过持久复制丙型肝炎病毒启动无效应子功能的抗病毒CD8 T细胞的启动。

尚不存在丙型肝炎病毒（HCV）的具有免疫功能的动物模型，这阻碍了宿主病毒相互作用和疫苗开发的研究。实验鼠感染鼠类肝炎病毒的方法是分离自鼠背鼠（RHV），这是一种很有希望的替代模型，因为它概括了HCV样的慢性病。但是，尚不清楚大鼠RHV感染的几个方面，例如，RHV如何逃避宿主的适应性免疫以建立持续性感染。在这里，我们分析了RHV特异性CD8 T细胞反应的诱导，分化和功能性，这些反应对于预防病毒持久性至关重要。在RHV感染后，针对主要和次要主要组织相容性复合物I类表位的病毒特异性CD8 T细胞在肝脏中大量增殖。这些人群长期忍受，但从未获得过抗病毒效应功能，也从未选择过进行病毒逃逸突变。这伴随着程序性细胞死亡-1的持续上调和缺乏记忆细胞的形成，与功能障碍的表型一致。值得注意的是，用直接作用的抗病毒剂短暂抑制RHV病毒血症导致启动了具有部分效应子功能的CD8 T细胞，从而推动了病毒逃逸变体的选择。这些数据证明了由大鼠RHV感染引发的CD8 T细胞内部的内在异常，这种影响至少部分由早期病毒复制的强度决定。因此，该模型可用于研究CD8 T细胞颠覆的机制，从而导致诸如HCV的肝病性病原体的持续存在。重要事项缺乏动物模型阻碍了丙型肝炎病毒（HCV）疫苗的开发，丙型肝炎是肝硬化和癌症的主要原因。HCV样啮齿动物肝炎病毒（RHV）的最新发现使这种模型在大鼠中得以发展。该平台概述了疫苗测试所必需的HCV肝细胞性和病毒慢性性。当前，很少有有关RHV特异反应的描述以及在该模型中为什么它们不能防止持续感染。在这里，我们显示RHV特异的CD8 T细胞虽然在早期被大量诱导，但并未发展为能够控制病毒的功能性效应子。通过使用HCV抗病毒药物进行短期治疗可以部分缓解这种缺陷。因此，与HCV一样，RHV引发病毒特异性CD8 T细胞功能异常，这对于解决感染至关重要。