Hepatitis B virus (HBV) infects the liver resulting in end stage liver disease, cirrhosis, and hepatocellular carcinoma. Despite an effective vaccine, HBV poses a serious health problem globally, accounting for 257 million chronic carriers. Unique features of HBV, including its narrow virus-host range and its hepatocyte tropism, have led to major challenges in the development of suitable in vivo and in vitro model systems to recapitulate the HBV replication cycle and to test various antiviral strategies. Moreover, HBV is classified into at least nine genotypes and 35 sub-genotypes with distinct geographical distributions and prevalence, which have different natural histories of infection, clinical manifestation, and response to current antiviral agents. Here, we review various in vitro systems used to study the molecular biology of the different (sub)genotypes of HBV and their response to antiviral agents, and we discuss their strengths and limitations. Despite the advances made, no system is ideal for pan-genotypic HBV research or drug development and therefore further improvement is required. It is necessary to establish a centralized repository of HBV-related generated materials, which are readily accessible to HBV researchers, with international collaboration toward advancement and development of in vitro model systems for testing new HBV antivirals to ensure their pan-genotypic and/or customized activity.

中文翻译：

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研究乙型肝炎病毒不同基因型/亚基因型的体外系统：优势和局限性。

乙型肝炎病毒（HBV）感染肝脏，导致晚期肝病，肝硬化和肝细胞癌。尽管有有效的疫苗，HBV在全球仍构成严重的健康问题，占2.57亿慢性携带者的总数。HBV的独特功能，包括狭窄的病毒宿主范围和肝细胞嗜性，已导致开发合适的体内和体外模型系统以概括HBV复制周期并测试各种抗病毒策略的重大挑战。此外，HBV至少分为9种基因型和35种亚基因型，具有不同的地理分布和流行程度，它们具有不同的自然感染史，临床表现和对当前抗病毒药物的反应。这里，我们回顾了用于研究HBV不同（亚）基因型的分子生物学及其对抗病毒剂反应的各种体外系统，并讨论了它们的优势和局限性。尽管取得了进步，但是对于泛基因型HBV研究或药物开发而言，尚无理想的系统，因此需要进一步改进。有必要建立一个与HBV相关的生成材料的集中存储库，HBV研究人员可以方便地访问它们，并与国际合作促进体外模型系统的发展和开发，以测试新的HBV抗病毒药物，以确保其泛基因型和/或定制化活动。没有系统适合进行全基因型HBV研究或药物开发，因此需要进一步改进。有必要建立一个集中的HBV相关产生物质的资料库，以供HBV研究人员随时使用，并与国际合作促进体外模型系统的发展和开发，以测试新的HBV抗病毒药以确保其泛基因型和/或定制化活动。没有系统适合进行全基因型HBV研究或药物开发，因此需要进一步改进。有必要建立一个集中的HBV相关产生物质的资料库，以供HBV研究人员随时使用，并与国际合作促进体外模型系统的发展和开发，以测试新的HBV抗病毒药以确保其泛基因型和/或定制化活动。