Hepatitis C virus infection and related liver disease: the quest for the best animal model.
Hepatitis C virus infection and related liver disease: the quest for the best animal model.
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DOI：
10.3389/fmicb.2013.00212
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发表时间：
2013
影响因子：
5.2
通讯作者：
Zeisel MB
中科院分区：
文献类型：
--
作者：
Mailly L;Robinet E;Meuleman P;Baumert TF;Zeisel MB
丙型肝炎病毒（HCV）是肝硬化和肝细胞癌（HCC）的主要原因，使病毒成为肝衰竭和肝移植的最常见原因。据估计，HCV每年慢性影响1.3亿人，并导致全球超过350，000人死亡。目前还没有疫苗。最近开发的直接作用抗病毒药物（DAA）显著提高了标准治疗的疗效，但不足以完全治愈所有慢性感染患者，并且其毒性限制了其在晚期肝病、合并症或移植受体患者中的使用。由于宿主限制，这是有限的人类和非人灵长类动物，在体内研究丙型肝炎病毒感染已被阻碍，因为它的发现超过20年前。黑猩猩仍然是研究先天性和适应性免疫反应的最生理模型，但它的使用在伦理上是困难的，现在受到非常严格的限制和管制。已经使用嵌合肝脏免疫缺陷小鼠实现了允许稳健HCV感染的小动物模型的开发，因此嵌合肝脏免疫缺陷小鼠不适合研究适应性免疫应答。然而，这些模型允许深入理解病毒-宿主相互作用并评估不同的治疗方法。最近通过遗传人源化建立的免疫活性小鼠模型在免疫应答研究方面显示出令人感兴趣的改进，但仍然受到缺乏病毒完整生命周期的限制。在这篇综述中，我们将重点介绍相关的可用的HCV感染的动物模型和它们的有用性破译HCV的生命周期和病毒引起的肝脏疾病，以及新的治疗方法的开发和评估。我们还将讨论未来免疫活性小鼠模型的前景及其发展的障碍。
Hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma (HCC) making the virus the most common cause of liver failure and transplantation. HCV is estimated to chronically affect 130 million individuals and to lead to more than 350,000 deaths per year worldwide. A vaccine is currently not available. The recently developed direct acting antivirals (DAAs) have markedly increased the efficacy of the standard of care but are not efficient enough to completely cure all chronically infected patients and their toxicity limits their use in patients with advanced liver disease, co-morbidity or transplant recipients. Because of the host restriction, which is limited to humans and non-human primates, in vivo study of HCV infection has been hampered since its discovery more than 20 years ago. The chimpanzee remains the most physiological model to study the innate and adaptive immune responses, but its use is ethically difficult and is now very restricted and regulated. The development of a small animal model that allows robust HCV infection has been achieved using chimeric liver immunodeficient mice, which are therefore not suitable for studying the adaptive immune responses. Nevertheless, these models allowed to go deeply in the comprehension of virus-host interactions and to assess different therapeutic approaches. The immunocompetent mouse models that were recently established by genetic humanization have shown an interesting improvement concerning the study of the immune responses but are still limited by the absence of the complete robust life cycle of the virus. In this review, we will focus on the relevant available animal models of HCV infection and their usefulness for deciphering the HCV life cycle and virus-induced liver disease, as well as for the development and evaluation of new therapeutics. We will also discuss the perspectives on future immunocompetent mouse models and the hurdles to their development.
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