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乙型肝炎动物模型的研究现状与挑战
DOI: 10.12449/JCH260105
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摘要: 乙型肝炎病毒（HBV）感染是全球面临的主要健康问题之一，是导致肝硬化和肝细胞癌的重要病因之一。由于HBV感染具有严格的种属特异性，目前尚未建立能够支持完整HBV感染周期并真实模拟宿主免疫和发病机制的动物模型。现有用于HBV研究的动物模型包括黑猩猩、树鼩和小鼠等多种宿主，以及利用相关嗜肝病毒建立的替代模型。尽管这些模型在研究HBV复制、免疫反应及抗病毒药物评估方面发挥了重要作用，但仍存在伦理、感染效率低、成本高或缺乏持续感染等局限。近年来，人源化肝脏与免疫系统的小鼠模型、转基因模型及病毒载体介导的感染模型等新策略的出现，显著推动了HBV生物学研究进展。未来，通过结合基因编辑、组织工程及多系统整合等新技术，构建更符合人类病理生理特征的HBV感染动物模型，将为深入理解病毒-宿主互作机制、探索HBV清除途径及开发根治性治疗策略提供坚实基础。Abstract: Hepatitis B virus （HBV） infection is one of the major global health problems， and it can lead to the development of liver cirrhosis and hepatocellular carcinoma. Due to the strict species specificity of HBV infection， no animal model has yet been established to fully support the complete life cycle of HBV infection and accurately reflect host immune responses and pathogenesis. Current animal models used for HBV research include various hosts such as chimpanzees， tree shrews， and mice， as well as surrogate models based on related hepatotropic viruses. Although these models have contributed significantly to the research on HBV replication， immune response， and antiviral drug evaluation， they still have certain limitations such as ethical concerns， low infection efficiency， high costs， and a lack of persistent infection. In recent years， the development of novel strategies， such as humanized mouse models with reconstituted human liver and immune systems， transgenic models， and viral vector-mediated infection systems， has greatly promoted the research on HBV biology. In the future， with the integration of emerging technologies including gene editing， tissue engineering， and multi-system reconstruction， it is possible to establish HBV infection models that can more closely mimic human pathophysiology， thereby laying a robust foundation for understanding virus-host interactions， exploring the pathways for viral clearance， and developing radical treatment strategies.
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Key words:
- Hepatitis B Virus /
- Covalently Closed Circular DNA /
- Models， Animal
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注： HBV生活周期包括病毒吸附、进入、脱衣壳、向细胞核的运输、cccDNA形成、转录、翻译、组装、分泌和整合。HBV，乙型肝炎病毒；HSPG，硫酸乙酰肝素蛋白聚糖；NTCP，钠离子-牛磺胆酸共转运多肽；HBeAg，乙型肝炎e抗原；MVB，多囊泡体；HBx，HBV X蛋白；HBsAg，乙型肝炎表面抗原；pgRNA，前基因组RNA；cccDNA，共价闭合环状DNA；dslDNA，双链线性DNA。
图 1 HBV生活周期
Figure 1. HBV life cycle
表 1 不同物种肝细胞对HBV感染与复制的支持能力
Table 1. Ability of hepatocytes from different species to support HBV infection and replication
物种 HBV进入 cccDNA形成及病毒
复制参考文献 人 + + ［3，11-13］ 黑猩猩 + + ［14-17］ 树鼩 + + ［3，13］ 土拨鼠 + - ［13］ 猕猴 - + ［3，13，18］ 食蟹猴 - + ［3，11-12］ 马 + + ［13］ 牛 +/- - ［12-13］ 山羊 +/- - ［12-13］ 猫 + + ［12-13］ 兔 + - ［12-13，19］ 仓鼠 - + ［12-13，20］ 豚鼠 - - ［12］ 猪 - + ［11-12，19］ 狗 + - ［11-12］ 大鼠 + - ［11］ 小鼠 - - ［10-11，21］ 注：“+”表示有；“-”表示无；“+/-”表示现有数据存在冲突。HBV，乙型肝炎病毒；cccDNA，共价闭合环状DNA。
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表 2 HBV小鼠模型
Table 2. HBV mice model
小鼠模型 载体/病毒
类型病毒
进入感染性 病毒
复制病毒持
久性cccDNA 病毒颗
粒分泌免疫系统 优势 局限性 HBV转基因
小鼠整合HBV
基因- - + + - + 免疫完全 易获取；近交
系；稳定表达
HBV基因非自然感染；无
cccDNA形成；无
病毒清除；免疫
耐受高压水动力
注射介导的
HBV转染小鼠HBV复制
型质粒- - + + - + 免疫完全 易获取；近交
系；研究病毒
清除机制非自然感染；瞬
时载体驱动的复
制；转染效率低；
复制时间短重组AdV介
导的HBV
转导小鼠AdV-HBV - - + +/剂量依赖 - + 免疫完全 易获取；近交
系；稳定复制非自然感染；无
cccDNA形成；剂
量依赖重组AVV介
导的HBV转
导小鼠AAV-HBV - - + +/剂量和品
系依赖+ + 免疫完全 易获取；近交
系；稳定复制；
支持cccDNA
形成非自然感染；无
病毒清除；剂量
和品系依赖；免
疫耐受cccDNA
替代小鼠重组
cccDNA- - + + + + 免疫完全 易获取；近交
系；稳定复制；
以cccDNA或
其替代分子为
复制模板非自然感染 人-鼠嵌合肝
脏小鼠HBV + + + + + + 免疫缺陷 易获取；近交
系；HBV易感感染过程缓慢；
造模操作复杂；
繁殖困难；免疫
缺陷人免疫系统
和肝双人源
化小鼠HBV + + + + + + 人的免疫
系统易获取；近交
系；HBV易感造模操作复杂；
繁殖困难；成本
较高注：“+”表示有或包含；“-”表示无或没有。HBV，乙型肝炎病毒；cccDNA，共价闭合环状DNA；AdV，腺病毒；AAV，腺相关病毒。
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