定量分析调控人类免疫缺陷病毒潜伏与激活的动力学机制
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上海大学物理系,定量生命科学国际研究中心,上海 200444

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国家自然科学基金(16Z103060007)资助项目。


A Quantitative Analysis of Dynamic Mechanisms Regulating HIV Latency and Activation
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Shanghai Center for Quantitative Life Sciences and Physics Department, Shanghai University, Shanghai 200444, China

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This work was supported by a grant from The National Natural Science Foundation of China (16Z103060007).

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    摘要:

    目的 治疗艾滋病最大的障碍在于无法根除人类免疫缺陷病毒(HIV)潜伏于人体细胞所形成的病毒存储库。构建描述病毒存储库建立分子机制的动力学模型需考虑生物体内的噪声环境和多重影响因素,本文通过一种全新的动力学结构分解方法将随机微分方程的确定性部分与随机性噪声分开,从而在仅需分析常微分方程不动点的情况下即可判断不同药物靶点的作用效果。方法 使用连续的随机微分方程构建了HIV转录过程的动力学模型,简化了描述系统所需方程的维度,增大了模型的可探索空间,在此基础上,通过计算得到的势能函数和概率分布函数直观表示病毒潜伏与激活的不同表达状态以及它们之间的关系。结果 定量分析了不同动力学参数对系统稳态和势函数的影响程度,分别得到了系统处于双稳态和单稳态时的参数范围,并将不同因素对动力系统分岔的影响程度与生物学实验结果对比,验证了本工作的理论基础。结论 本文突破了以往离散、随机的方法,可以通过常微分方程定量分析HIV转录调控的动力学机制,有利于推广到处理高维情况,进一步研究艾滋病在生物体内的发生发展,从而指导设计实验寻找临床上的治疗方案。

    Abstract:

    Objective The reservoir of human immunodeficiency virus (HIV) latently infected cells is the major obstacle for eradication of acquired immunodeficiency syndrome (AIDS). Due to the noisy environment and multiple influencing factors in the organism, current dynamical models cannot reach a common understanding of the molecular mechanism of HIV latency. In this work, through a new dynamical structure decomposition, the deterministic part of the equation can be separated from the stochastic noise. Thus, the fixed-point analysis of ordinary differential equation is enough to obtain the different steady states of the system.Methods We established a dynamical model of HIV transcription process by using continuous stochastic differential equations, which simplifies the dimensions of equations needed to describe the system and increases the explorable space of the model. Different states between latency and activation of virus and their relations can be intuitively represented by potential functions and probability distribution functions.Results Based on our model, the influence of different dynamical parameters on stability is quantitatively analyzed, the parameter ranges of the system in bistable and monostable states are obtained respectively. The theoretical basis of this work is verified by comparing the effects of different factors on dynamic bifurcation with the results of biological experiments.Conclusion This paper goes beyond previous discrete stochastic methods, and can quantitatively analyze the dynamic mechanism of HIV transcriptional regulation through ordinary differential equations, which is beneficial to the promotion to deal with the high-dimensional situation, and further study the occurrence and development of AIDS in vivo, so as to guide the design of experiments and search for clinical treatment.

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熊瑞琪,苏洋,敖平.定量分析调控人类免疫缺陷病毒潜伏与激活的动力学机制[J].生物化学与生物物理进展,2023,50(2):385-396

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  • 收稿日期:2022-02-15
  • 最后修改日期:2023-01-15
  • 接受日期:2022-05-09
  • 在线发布日期: 2023-02-22
  • 出版日期: 2023-02-20