The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection
The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection
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DOI：
10.1016/j.jtbi.2018.06.020
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发表时间：
2018-10-14
影响因子：
2
通讯作者：
Chauhan, Ranjit
中科院分区：
文献类型：
--
作者：
Goyal, Ashish;Chauhan, Ranjit
背景：在HBV感染的几个阶段中，最不为人所知的阶段是隐性乙型肝炎病毒感染。由于缺乏生物组织和检测隐匿性乙型肝炎病毒感染的超灵敏试验的先决条件，数据的缺乏促使我们利用数学模型来确定导致隐匿性乙型肝炎病毒感染的机制和隐匿性乙型肝炎病毒感染期间HBV感染的特征。方法：我们提出了两个数学模型（M1和M2），考虑了感染肝细胞中共价闭合环状DNA （cccDNA）的表观维持和积累的两种不同现象：(i) M1 -松弛环状DNA/双链线性DNA从细胞质到细胞核的再循环，以及（ii） M2 -感染肝细胞与病毒粒子的再感染。我们进一步纳入整合乙型肝炎病毒DNA （iHBV）的动力学，以研究其在隐性乙型肝炎病毒感染发展中的作用。结果：隐匿性乙型肝炎病毒感染时感染传播的主要机制是细胞间传播，而非无细胞传播。显著的病毒抑制（从其峰值产量至少减少99%）是必要的，但在M1下隐匿性乙型肝炎病毒感染的发展中是不够的；然而，在M2下，病毒抑制既不充分也不必要，因为抑制HBsAg的产生而不抑制病毒也可以解释隐匿性乙型肝炎病毒感染的发生。我们的分析还显示，隐匿性乙型肝炎病毒感染血清阳性的病例比隐匿性乙型肝炎病毒感染血清阴性的病例更有可能进展为肝硬化。在隐匿性乙型肝炎病毒感染期间，发现iHBV大部分是沉默的（要么是缺失的，要么是非HBsAg的）。结论：病毒抑制本身不是解释隐匿性乙型肝炎病毒感染发生的必要条件，也不是充分条件。除了病毒抑制外，cccDNA和iHBV对HBsAg产生和输出的抑制也在隐匿性乙型肝炎病毒感染的发展中起重要作用。这是第一个纳入iHBV动力学的研究，并表明HBV在隐性乙型肝炎病毒感染期间主要通过细胞-细胞传播传播。(C) 2018年Elsevier Ltd.出版
Background: Out of several phases of HBV infection, the least understood phase is occult hepatitis B virus infection. The paucity of data due to non-availability of biological tissues and the prerequisite of ultra sensitive assays for the detection of occult hepatitis B virus infection prompted us to utilize mathematical modeling in determining mechanisms that lead to occult hepatitis B virus infection and characteristics of HBV infection during occult hepatitis B virus infection.Methods: We proposed two mathematical models (M1 and M2), considering two different phenomenon for episomal maintenance and accumulation of covalently closed circular DNA (cccDNA) in infected hepatocytes: (i) M1 - recirculation of the relaxed circular DNA/double-stranded linear DNA from cytoplasm to the nucleus, and (ii) M2 - reinfection of infected hepatocytes with virions. We further incorporated the dynamics of integrated Hepatitis B virus DNA (iHBV) to investigate its role in the development of occult hepatitis B virus infection.Results: The analysis showed that the main mechanism for the spread of infection during occult hepatitis B virus infection is cell-to-cell transmission and not cell-free virus transmission. A significant viral suppression (of at least 99% from its peak production values) was essential but not sufficient in the development of occult hepatitis B virus infection under M1; however under M2, the viral suppression was neither sufficient nor essential as the inhibition of the production of HBsAg without viral suppression can also explain the development of occult hepatitis B virus infection. Our analysis also revealed that occult hepatitis B virus infection seropositive cases are more likely to progress into liver cirrhosis compared to occult hepatitis B virus infection seronegative cases. The iHBV was found to be mostly silent (by either being absent or non-productive for HBsAg) during occult hepatitis B virus infection.Conclusion: The viral suppression is neither essential nor sufficient to explain the development of occult hepatitis B virus infection on its own. Not only the viral suppression but the inhibition-of the production and the export of HBsAg from cccDNA and iHBV also plays an important role in the development of occult hepatitis B virus infection. This is the first study, which incorporates the dynamics of iHBV and shows that HBV primarily spreads via cell-cell transmission during occult hepatitis B virus infection. (C) 2018 Published by Elsevier Ltd.