Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, United States.
J Theor Biol. 2021 Oct 7;526:110793. doi: 10.1016/j.jtbi.2021.110793. Epub 2021 Jun 1.
Hepatitis B virus (HBV) with its high prevalence and death toll is one of the most important infectious diseases to study. Yet, there is very little progress in the development of within-host models for HBV, which has subsequently hindered our understanding of this virus. The uncertainty around the proliferation of infected hepatocytes has been studied but never in association with other important biological continuous events such as integrations and superinfections. This is despite the fact that these processes affect the diversity and composition of infected cell population in the liver and an improved understanding of the cellular composition will undoubtedly assist in strategizing against this viral infection. Here, we developed novel mathematical models that incorporate these key biological processes and analyzed them both analytically and numerically. Unaffected by the extent of integrated DNA (IDNA), the outcome of HBV infection was primarily dictated by the balance between processes generating and killing infected hepatocytes containing covalent closed circular DNA (cccDNA). The superinfection was found to be a key process in the spread of HBV infection as its exclusion could not reproduce experimentally observed composition of infected hepatocytes at peak of acute HBV infection, a stage where our model predicts that infected hepatocytes most likely carry both cccDNA and IDNA. Our analysis further suggested the existence of some form of selective advantage of infected hepatocytes containing only IDNA to explain the viral dynamics observed during antiviral treatment and the transition from peak to acute infection. Finally, the fine line between liver destruction and resolution of acute HBV infection was found to be highly influenced by the fate of cccDNA during cellular proliferation.
乙型肝炎病毒 (HBV) 具有高发病率和死亡率，是研究最重要的传染病之一。然而，HBV 体内模型的发展进展甚微，这也阻碍了我们对该病毒的理解。尽管这些过程会影响肝脏中受感染细胞群体的多样性和组成，但受感染肝细胞增殖的不确定性一直受到研究，但从未与其他重要的生物连续事件（如整合和超感染）联系起来。事实上，这些过程会影响肝脏中受感染细胞群体的多样性和组成，对细胞组成的更好理解无疑将有助于对抗这种病毒感染。在这里，我们开发了新的数学模型，将这些关键的生物学过程纳入其中，并对它们进行了分析。受整合 DNA (IDNA) 程度的影响，HBV 感染的结果主要取决于产生和杀死含有共价闭合环状 DNA (cccDNA) 的受感染肝细胞的过程之间的平衡。超感染被发现是 HBV 感染传播的关键过程，因为其排除不能复制在急性 HBV 感染高峰期观察到的受感染肝细胞的组成，在这个阶段，我们的模型预测受感染的肝细胞最有可能携带 cccDNA 和 IDNA。我们的分析进一步表明，仅含有 IDNA 的受感染肝细胞存在某种形式的选择性优势，以解释抗病毒治疗期间和从高峰到急性感染的过渡期间观察到的病毒动力学。最后，在细胞增殖过程中，cccDNA 的命运对急性 HBV 感染的缓解和消退之间的细微差别产生了很大的影响。
