丙型肝炎的慢性化机理和传播机制的数学建模与研究

Hepatitis C virus (HCV) is currently recognized as one of the main causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. So far, no effective vaccine has been developed to prevent the transmission of HCV. We shall investigate the mechanism of hepatitis C chronicity by means of theories of viral dynamics, immune dynamics and adaptive dynamics, and study the mechanism of HCV transmission by establishing the nested models between the infection in vivo and the transmission between individuals. Based on the mechanism of HCV infection in vivo, the maturing processes of dentritic cell (DC)-the most important antigen-presenting cells for host immune responses, and the action of DC on activating T lymphocytes, we will establish the dynamical models of DC during HCV infection, analyze the effects of DC and host immune systems on HCV infection, investigate the mechanisms of HCV immune escape and quasispecies production by means of the theory of adaptive dynamics, explore the mechanism leading to the chronicity of HCV infection according to the clinical data, and provide the theoretical guidance and basis for clinically treating hepatitis C and recognizing the evolution rules of HCV. We also establish mathematical models for coupling with-host and between-host dynamics of HCV infection, analyze the mutual effects between microcosmic infection and macrocosmic transmission of HCV, explore their coupling patterns, determine the associated thresholds, and provide the decision-making basis for controlling the transmission of Hepatitis C. And we will further develop the related theories and methods on applied mathematics with respect to mathematical modeling, adaptive dynamics and higher- dimensional dynamical systems in researching processes.The obtained results will also enrich and develop the related dynamical theory

丙型肝炎病毒(HCV)的慢性感染可导致部分患者发展为肝硬化甚至肝癌，对患者的健康乃至生命危害极大。至今尚未开发出有效的丙肝疫苗。树突状细胞(DC)是最有效的抗原提呈细胞，对HCV在人体内的感染起着关键的作用。本项目首先根据HCV在人体内的感染机理、DC的成熟过程以及DC在激活T细胞方面的作用，借助病毒动力学和免疫动力学，建立HCV感染过程中DC的动力学模型，分析DC和免疫系统在HCV感染过程中的作用；然后用适应动力学的研究方法，研究HCV的免疫逃逸机理和准种产生机制，并根据临床观察资料，探究丙型肝炎的慢性化机理，为临床治疗丙型肝炎和认识HCV的演变规律提供理论基础。再鉴于HCV的微观感染和宏观传播的相互影响，探寻两者间的耦合模式，建立相应的嵌套模型，借助奇异摄动理论，确定HCV感染和传播的相关阈值，为理解丙型肝炎的传播机制和控制其传播提供理论依据。其研究成果也将丰富和发展相关的动力学理论。

丙肝病毒的感染与传播严重威胁人类的健康乃至生命。本项目从DC在HCV感染过程的作用与HCV免疫逃逸和准种的产生两个方面研究了HCV的体内感染机理，通过将HCV的体内感染与个体间传播的动力学模型进行嵌套耦合研究了HCV的传播机制。在感染机理方面，就DC的成熟过程和DC激活CTL的不同形式建立具有免疫作用的数学模型，研究免疫系统对HCV感染的影响机制以及在慢性感染过程中的抑制作用，发现DC固定成熟期的假设会导致模型出现周期解和混动现象，以及DC激活CTL的饱和型函数会使系统出现后向分支，从而HCV的感染结果会依赖于模型的初始状态，为进一步了解HCV感染过程中免疫系统的作用机理提供理论指导；通过考虑肝细胞的不同增长方式与HCV免疫逃逸和准种的产生，建立HCV的感染动力学模型，分析HCV 存在不同亚型和对应抗体或准种存在时的模型动力学性态，发现肝细胞的logistic增长方式假设使模型会发生Hopf分支，从而会出现模型周期解；HCV的免疫逃逸毒株使得感染者的机体免疫系统难以对HCV感染发挥有效的抑制作用，以及准种的存在对肝移植后的治疗效果具有严重的影响，这些为理解HCV的感染机理提供理论依据。在HCV传播机制方面，考虑感染者体内的病毒载量对传染力的影响，建立微观感染模型嵌套于宏观传播模型的微观宏观耦合模型，分析感染者不同嵌套形式下的感染力对宏观传播结局的影响，发现饱和型嵌套函数使模型具有复杂的动力学性态，为探讨控制HCV传播提供了多方面的考虑措施。