Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.
Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.
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DOI：
10.1371/journal.pone.0161978
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Murray JM
中科院分区：
文献类型：
--
作者：
Goyal A;Murray JM
无细胞病毒是一种公认的有效的机制，为B型肝炎病毒（HBV）感染的传播在肝脏。细胞间传播（CCT）可能是一种更有效的病毒传播方式。尽管实验证据表明CCT发生在HBV中，但其相对影响尚不确定。我们开发了一个3-D的代理为基础的模型，每个肝细胞改变其病毒状态，根据一个动态过程驱动的无细胞病毒感染，CCT和细胞内复制。我们确定CCT在细胞溶解（CTL）和非CTL机制存在下急性HBV感染的发展和解决中的相对重要性。T细胞清除数定义为在峰值感染时每个T细胞需要杀死的感染细胞的最小数量，该数量导致12周内感染清除，肝细胞更新（HT，等效肝脏数量）≤3。我们发现CCT对感染的建立几乎没有影响，因为无论CCT强度如何，平均cccDNA拷贝/细胞在感染高峰时保持在15至20之间。相比之下，CCT抑制免疫介导的急性HBV感染的清除，因为更高的CCT强度需要更高的T细胞清除数，并增加T细胞耗竭的可能性。有效的非CTL抑制可以通过支持快速、有效的病毒清除和很少的肝脏破坏来抵消更高强度CCT的这些负面影响。这是明显的，因为当非CTL抑制从10%增加到80%时，T细胞清除数下降约50%。更高的CCT强度也增加了暴发性肝炎发生率的可能性，而这种现象不太可能在没有CCT的情况下发生。总之，我们报告了CCT影响HBV清除的可能性及其对重型肝炎的贡献。
Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms. T cell clearance number is defined as the minimum number of infected cells needed to be killed by each T cell at peak infection that results in infection clearance within 12 weeks with hepatocyte turnover (HT, number of equivalent livers) ≤3. We find that CCT has very little impact on the establishment of infection as the mean cccDNA copies/cell remains between 15 to 20 at the peak of the infection regardless of CCT strength. In contrast, CCT inhibit immune-mediated clearance of acute HBV infection as higher CCT strength requires higher T cell clearance number and increases the probability of T cell exhaustion. An effective non-CTL inhibition can counter these negative effects of higher strengths of CCT by supporting rapid, efficient viral clearance and with little liver destruction. This is evident as the T cell clearance number drops by approximately 50% when non-CTL inhibition is increased from 10% to 80%. Higher CCT strength also increases the probability of the incidence of fulminant hepatitis with this phenomenon being unlikely to arise for no CCT. In conclusion, we report the possibility of CCT impacting HBV clearance and its contribution to fulminant hepatitis.