Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Virology Researcher, St Johns, Canada.
J Theor Biol. 2018 Oct 14;455:269-280. doi: 10.1016/j.jtbi.2018.06.020. Epub 2018 Jun 30.
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.
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.
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.
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.
在乙型肝炎病毒（HBV）感染的几个阶段中，最不为人知的阶段是隐匿性乙型肝炎病毒感染。由于缺乏生物组织，并且需要超灵敏检测方法来检测隐匿性乙型肝炎病毒感染，因此数据很少，这促使我们利用数学建模来确定导致隐匿性乙型肝炎病毒感染的机制以及隐匿性乙型肝炎病毒感染期间 HBV 感染的特征。
我们提出了两个数学模型（M1 和 M2），考虑了两种不同的现象，即游离环状 DNA/双链线性 DNA 从细胞质循环到核内以及感染肝细胞中共价闭合环状 DNA（cccDNA）的积累：（i）M1-松弛环状 DNA/双链线性 DNA 从细胞质循环到核内，以及（ii）M2-感染肝细胞的再感染。我们进一步纳入了整合乙型肝炎病毒 DNA（iHBV）的动力学，以研究其在隐匿性乙型肝炎病毒感染发展中的作用。
分析表明，隐匿性乙型肝炎病毒感染期间感染传播的主要机制是细胞间传播，而不是无细胞病毒传播。在 M1 中，至少从其峰值产生值降低 99%是隐匿性乙型肝炎病毒感染发展的必要但非充分条件；然而，在 M2 中，病毒抑制既不是必要的也不是充分的，因为没有病毒抑制而抑制 HBsAg 的产生也可以解释隐匿性乙型肝炎病毒感染的发展。我们的分析还表明，与隐匿性乙型肝炎病毒感染阴性病例相比，隐匿性乙型肝炎病毒感染阳性病例更有可能发展为肝硬化。在隐匿性乙型肝炎病毒感染期间，iHBV 大多处于沉默状态（要么不存在，要么不能产生 HBsAg）。
仅病毒抑制不足以单独解释隐匿性乙型肝炎病毒感染的发展。不仅病毒抑制，而且抑制-HBsAg 从 cccDNA 和 iHBV 的产生和输出也在隐匿性乙型肝炎病毒感染的发展中起着重要作用。这是第一项整合 iHBV 动力学的研究，并表明 HBV 主要通过细胞间传播在隐匿性乙型肝炎病毒感染期间传播。
