HBV DNA整合：分子机制和临床意义

StephenW

Viruses 2017, 9(4), 75; doi:10.3390/v9040075
Review
HBV DNA Integration: Molecular Mechanisms and Clinical Implications
Thomas Tu 1,*, Magdalena A. Budzinska 2,3, Nicholas A. Shackel 2,3,4 and Stephan Urban 1,5
1Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
2Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia
3Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia
4Liverpool Hospital, Gastroenterology, Sydney, NSW 2170, Australia
5German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
*
Correspondence: Tel.: +49-6221-564908
Academic Editors: Ulrike Protzer and Michael Nassal

Received: 2 March 2017 / Accepted: 4 April 2017 / Published: 10 April 2017

Abstract: Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies.
Keywords:
hepatitis B virus; integration; hepatocellular carcinoma; non-homologous end joining; viral persistence

StephenW

病毒2017，9（4），75; doi：10.3390 / v9040075
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HBV DNA整合：分子机制和临床意义
Thomas Tu 1，*，Magdalena A. Budzinska 2,3，Nicholas A. Shackel 2,3,4和Stephan Urban 1,5
海德堡大学分子病毒学传染病研究室，Im Neuenheimer Feld 345,69120德国海德堡
悉尼大学，悉尼，新南威尔士州2050澳大利亚科学研究所
悉尼大学3悉尼医学院，悉尼，新西兰2006年，澳大利亚
4利物浦医院，消化内科，悉尼，新南威尔士州2170，澳大利亚
5German感染研究中心（DZIF），海德堡合作伙伴网站，Im Neuenheimer Feld 345,69120德国海德堡
*
通讯：电话：+ 49-6221-564908
学术编辑：Ulrike Protzer和Michael Nassal

收到：2017年3月2日/接受：2017年4月4日/发布时间：2017年4月10日

摘要：乙型肝炎病毒（HBV）的慢性感染是肝脏相关发病率和死亡率的主要原因。感染HBV（或与密切相关的动物肝素病毒）的细胞中的一个特殊观察是病毒DNA整合在宿主细胞基因组中的存在，尽管这种形式是病毒的复制死端。经常发现病毒DNA的体细胞整合表明病毒的进化益处;然而，整合的机制，其功能和临床意义仍然未知。在这里，我们回顾当前的HBV DNA整合知识体系，特别关注分子机制及其临床意义（包括与复制无关的抗原表达的可能后果及其在肝细胞癌中的可能作用）。 HBV DNA整合可能影响HBV复制，持续性和发病机制，因此在未来的研究中值得更多关注。
关键词：
乙型肝炎病毒;积分;肝细胞癌;非同源末端连接;病毒持久性

StephenW

4. Conclusions
With the scant available knowledge of its molecular mechanisms, roles in virus replication, and clinical implications, HBV DNA integration remains an intriguing phenomenon that still requires intense study. Particular focus should be placed on integration and its involvement in HBV replication and persistence, which underpins our understanding of how to develop a cure for CHB patients. Much of our understanding has been extrapolated from animal models, but many important unanswered questions on the role of HBV integration (especially with respect to its role in HBV chronicity and HCC development) remain and may be addressed using recently-developed, physiologically-relevant cell culture and in vivo infection models, such as humanized mice. Of course, these models must ultimately provide physiological relevance and accuracy. As such, studies based on human liver tissue samples are indispensable to gain insights about the biological and clinical significance of HBV integration. While the exact function of HBV DNA integration is unknown at this time, further investigation of this feature that is shared by all known members of the Hepadnaviridae will undoubtedly improve our understanding of the persistence, progression, and pathogenesis of chronic HBV infections.

4。结论
随着其分子机制，病毒复制的作用和临床意义的可用知识的不足，HBV DNA整合仍然是一个有趣的现象，仍然需要深入研究。应特别重视整合及其参与HBV复制和持续性，这为我们对如何开发治愈CHB患者的了解提供了依据。我们的大部分理解已经从动物模型推断出来，但是关于HBV整合的作用（特别是其在HBV慢性和HCC发展中的作用方面）的许多重要的未回答的问题仍然存在，并且可以使用最近开发的生理相关细胞来解决培养和体内感染模型，如人源化小鼠。当然，这些模型必须最终提供生理相关性和准确性。因此，基于人肝组织样本的研究对于获得有关HBV整合的生物学和临床意义的见解是不可或缺的。虽然HBV DNA整合的确切功能目前还不得而知，Hepadnaviridae所有已知成员共享的这一特征的进一步调查无疑将提高我们对慢性HBV感染的持续性，进展和发病机理的认识。

StephenW

http://www.mdpi.com/1999-4915/9/4/75/htm