生命周期同步是一种病毒耐药机制。

StephenW

PLoS Comput Biol. 2018 Feb 15;14(2):e1005947. doi: 10.1371/journal.pcbi.1005947. eCollection  2018 Feb.
Life cycle synchronization is a viral drug resistance mechanism.Neagu IA1,2, Olejarz J1, Freeman M1, Rosenbloom DIS3, Nowak MA1, Hill AL1.
Author information
1Program for Evolutionary Dynamics, Department of Mathematics and Department of Organismic & Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.2Department of Physics, Harvard University, Cambridge, Massachusetts, United States of America.3Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, United States of America.

AbstractViral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for clinically relevant antiviral strategies.


PMID:29447150DOI:10.1371/journal.pcbi.1005947

StephenW

PLoS Comput Biol。 2018年2月15日; 14（2）：e1005947。 doi：10.1371 / journal.pcbi.1005947。 eCollection 2018年2月
生命周期同步是一种病毒耐药机制。
Neagu IA1,2，Olejarz J1，Freeman M1，Rosenbloom DIS3，Nowak MA1，Hill AL1。
作者信息

1
    美国马萨诸塞州剑桥哈佛大学数学系和进化生物学系进化动力学课程。
2
    哈佛大学物理系，美国马萨诸塞州剑桥市。
3
    美利坚合众国纽约哥伦比亚大学医学中心生物医学信息学系。

抽象

病毒感染是全球死亡的主要原因之一，仅艾滋病毒感染就造成每年超过120万人的伤亡。目前，抗病毒药物正在用于各种病毒感染，包括艾滋病毒，乙型肝炎和丙型肝炎，以及流感。这些疗法针对病毒生命周期的特定阶段，但其最终成功取决于各种因素，如遵守规定的方案和出现病毒耐药性。流行病学和耐药性的演变已被广泛表征，并且通常认为耐药性是由改变病毒对药物直接作用易感性的突变引起的。在本文中，我们考虑了病毒群体可能朝着使其生命周期与药物治疗模式同步的方向发展的可能性。然后，药物治疗的周期性可以允许仅当药物浓度最低时，其生命周期长度是给药间隔的倍数的病毒株复制。这个过程被称为“同步药物耐受性”，可以使病毒群体最大限度地发挥其整体适应性，而无需改变药物结合或完成药物存在的生命周期。我们使用数学模型和随机模拟来表明生命周期同步确实可以成为病毒耐药性的机制。我们表明，当病毒生命周期和药物剂量定时的变异性较低时，这种效应更可能发生。更一般地说，我们发现在存在定期药物水平的情况下，即使没有同步化，病毒适应性的时间平均计算也不能准确预测根除感染所需的药物水平。我们推导出一个病毒适应性的分析表达式，足以解释任何生命周期长度的菌株的药物模式依赖性存活。我们讨论这些研究结果对临床相关抗病毒策略的影响。

结论：
    29447150
DOI：
    10.1371 / journal.pcbi.1005947

StephenW

非常有意义的考虑[stephenw]

"尽管我们已经表明，通过生命周期同步的耐受性是一种可以在计算机上回避治疗的可能手段，据我们所知，这种影响从未经过实验评估。"

http://journals.plos.org/ploscom ... ournal.pcbi.1005947