Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1(0 1):120-4. doi: 10.1111/jgh.12092.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect and replicate primarily in human hepatocytes. Few reliable and easy accessible animal models are available for studying the immune system's contribution to the liver disease progression during hepatitis virus infection. Humanized mouse models reconstituted with human hematopoietic stem cells (HSCs) have been developed to study human immunology, human immunodeficiency virus 1 infection, and immunopathogenesis. However, a humanized mouse model engrafted with both human immune and human liver cells is needed to study infection and immunopathogenesis of HBV/HCV infection in vivo. We have recently developed the humanized mouse model with both human immune and human liver cells (AFC8-hu HSC/Hep) to study immunopathogenesis and therapy of HCV infection in vivo. In this review, we summarize the current models of HBV/HCV infection and their limitations in immunopathogenesis. We will then present our recent findings of HCV infection and immunopathogenesis in the AFC8-hu HSC/Hep mouse, which supports HCV infection, human T-cell response and associated liver pathogenesis. Inoculation of humanized mice with primary HCV isolates resulted in long-term HCV infection. HCV infection induced elevated infiltration of human immune cells in the livers of HCV-infected humanized mice. HCV infection also induced HCV-specific T-cell immune response in lymphoid tissues of humanized mice. Additionally, HCV infection induced liver fibrosis in humanized mice. Anti-human alpha smooth muscle actin (αSMA) staining showed elevated human hepatic stellate cell activation in HCV-infected humanized mice. We discuss the limitation and future improvements of the AFC8-hu HSC/Hep mouse model and its application in evaluating novel therapeutics, as well as studying both HCV and HBV infection, human immune responses, and associated human liver fibrosis and cancer.
乙型肝炎病毒 (HBV) 和丙型肝炎病毒 (HCV) 主要感染和复制人体肝细胞。目前可用于研究病毒感染期间免疫系统对肝脏疾病进展的影响的可靠且易于获取的动物模型较少。用人造血干细胞 (HSCs) 重建的人源化小鼠模型已被开发用于研究人类免疫学、人类免疫缺陷病毒 1 感染和免疫发病机制。然而，需要一种同时植入人免疫细胞和人肝细胞的人源化小鼠模型来研究 HBV/HCV 感染的体内感染和免疫发病机制。我们最近开发了一种同时具有人免疫细胞和人肝细胞的人源化小鼠模型 (AFC8-hu HSC/Hep)，用于研究 HCV 感染的体内免疫发病机制和治疗。在这篇综述中，我们总结了 HBV/HCV 感染的当前模型及其在免疫发病机制中的局限性。然后，我们将介绍我们最近在 AFC8-hu HSC/Hep 小鼠中 HCV 感染和免疫发病机制的发现，该模型支持 HCV 感染、人 T 细胞反应和相关的肝脏发病机制。用原发性 HCV 分离株接种人源化小鼠可导致长期 HCV 感染。HCV 感染诱导 HCV 感染的人源化小鼠肝脏中人类免疫细胞的浸润增加。HCV 感染还诱导人源化小鼠淋巴组织中的 HCV 特异性 T 细胞免疫反应。此外，HCV 感染诱导人源化小鼠肝纤维化。抗人α平滑肌肌动蛋白 (αSMA) 染色显示 HCV 感染的人源化小鼠中人类肝星状细胞激活增加。我们讨论了 AFC8-hu HSC/Hep 小鼠模型的局限性和未来改进及其在评估新型治疗药物、研究 HCV 和 HBV 感染、人类免疫反应以及相关的人类肝纤维化和癌症中的应用。
