Computer Simulation of Epstein Barr Virus Infection

描述（由申请人提供）：eb病毒持续感染95%的成年人。它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利用潜伏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。这使得EBV在血液中静止记忆B细胞中建立潜伏的持续性感染，并在瓦尔德耶氏环淋巴上皮（扁桃体和腺样体）的浆细胞中复制。然而，这些研究都是静态的，缺乏对感染动态的理解。在缺乏合适的动物模型的情况下，我们建议开发新一代的计算机模拟。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程度。我们将采用一种基于主体的方法，这使得有可能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无法实现的。根据以往对交通和无线通信系统的类似模拟的经验，一个涉及大约108个代理的模拟是可以实现的，应该会产生现实的结果。我们将使用敏感的PCR和免疫学技术来准确测量病毒脱落水平，病毒感染细胞，EBV特异性CD4和CD8细胞和中和抗体，因为急性感染演变为持续感染。这些数据将被用于计算机模拟。这种方法将允许我们定义必要的感染参数来预测观察到的感染动力学。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）消除传染性病毒（抗病毒和/或疫苗），并询问完全清除（即治愈）病毒是否现实或甚至可能。

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.