Computer Simulation of Epstein Barr Virus Infection

EB 病毒感染的计算机模拟

• 批准号: 7174842
• 负责人: David A. Thorley-Lawson
• 金额: $ 43.44万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174842
• 关键词: Ablation; Acute; Address; Adenoidal structure; Adult; Algorithms; Anatomy; Animal Model; B-Lymphocytes; Biology; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Communication; Computer Simulation; Data; Dose; Epstein-Barr Virus Infections; Equation; Equilibrium; Generations; Goals; Herpesviridae; Human; Human Herpesvirus 4; Immune; Immunologic Techniques; Immunologics; Immunosuppression; Infection; Infectious Mononucleosis; Intervention; Kinetics; Linux; Lymphocyte; Malignant Neoplasms; Measurement; Measures; Memory B-Lymphocyte; Modeling; Numbers; Organ; Output; Pattern; Plasma Cells; Polymerase Chain Reaction; Population; Population Sizes; Production; Rest; Running; Saliva; Simplexvirus; Supercomputing; System; T-Lymphocyte; Target Populations; Technology; Testing; Therapeutic immunosuppression; Time; Tissues; Tonsil; Transplant Recipients; Vaccination; Vaccines; Variant; Viral; Viral Antibodies; Virus; Virus Shedding; Wireless Technology; base; experience; immunosuppressed; latent gene expression; latent persistent infection; mathematical model; neutralizing antibody; pathogen; response; simulation; trafficking

DESCRIPTION (provided by applicant): Epstein-Barr vires persistently infects >95% of the adult human population. It causes infectious mononucleosis and is associated with several important human cancers. Considerable progress has been made recently in understanding how EBV establishes and maintains persistent infection. It is apparent that EBV uses various combinations of latent gene expression patterns to manipulate the biology of normal B lymphocytes. This allows EBV to establish latent persistent infection in resting memory B cells in the blood and replicate in plasma cells in the lymphoepithelium of Waldeyer's ring (tonsils and adenoids). However, these studies have all been static and an understanding of the dynamics of the infection is lacking. In the absence of a suitable animal model, we propose to develop a new generation of computer simulation. The application of supercomputing on distributed clusters of processors will allow us to develop an unprecedented level of sophistication and complexity. We will employ an agent-based approach, which makes it possible to represent the actual anatomy of the relevant tissues and organs and the dynamic changes that occur over time and space. These features are not possible with traditional mathematical models based on ordinary differential equations. A simulation involving approximately 108 agents is within reach and should produce realistic results, based on previous experience with similar simulations of traffic and wireless communication systems. We will use sensitive PCR and immunological techniques to accurately measure levels of virus shedding, virus infected cells, EBV specific CD4 and CD8 cells and neutralizing antibody as acute infection resolves into persistent infection. The data will then be used to inform the computer simulation. This approach will allow us to define the infection parameters necessary to predict the observed kinetics of infection. Ultimately, the simulation will be used to test the effects of perturbations such as lowering the numbers of T cells (immunosuppression) eliminating infectious virus (anti-viral and/or vaccines) and to ask if complete clearance (i.e. cure) of the virus is realistic or even possible.

描述（由申请人提供）：EB 病毒持续感染超过 95% 的成年人口。它会引起传染性单核细胞增多症，并与几种重要的人类癌症有关。最近在了解 EBV 如何建立和维持持续感染方面取得了相当大的进展。很明显，EBV 使用潜在基因表达模式的各种组合来操纵正常 B 淋巴细胞的生物学特性。这使得 EBV 在血液中的静息记忆 B 细胞中建立潜伏的持续感染，并在韦氏环（扁桃体和腺样体）的淋巴上皮细胞中复制。然而，这些研究都是静态的，缺乏对感染动态的了解。在缺乏合适的动物模型的情况下，我们建议开发新一代计算机模拟。超级计算在分布式处理器集群上的应用将使我们能够开发出前所未有的复杂性和复杂性。我们将采用基于代理的方法，这使得能够表示相关组织和器官的实际解剖结构以及随时间和空间发生的动态变化。这些特征是基于常微分方程的传统数学模型不可能实现的。根据之前对交通和无线通信系统进行类似模拟的经验，涉及大约 108 个代理的模拟是可以实现的，并且应该会产生真实的结果。当急性感染转化为持续性感染时，我们将使用灵敏的 PCR 和免疫学技术来准确测量病毒脱落、病毒感染细胞、EBV 特异性 CD4 和 CD8 细胞以及中和抗体的水平。然后，这些数据将用于为计算机模拟提供信息。这种方法将使我们能够定义预测观察到的感染动力学所需的感染参数。最终，模拟将用于测试扰动的影响，例如降低 T 细胞数量（免疫抑制）、消除感染性病毒（抗病毒和/或疫苗），并询问完全清除（即治愈）病毒是否现实或什至可能。