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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062989-02
Application #
7005691
Study Section
Special Emphasis Panel (ZRG1-MABS (01))
Program Officer
Beisel, Christopher E
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$438,244
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Roughan, Jill E; Torgbor, Charles; Thorley-Lawson, David A (2010) Germinal center B cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol 84:1158-68
Roughan, Jill E; Thorley-Lawson, David A (2009) The intersection of Epstein-Barr virus with the germinal center. J Virol 83:3968-76
Delgado-Eckert, Edgar (2009) Reverse engineering time discrete finite dynamical systems: a feasible undertaking? PLoS One 4:e4939
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Shapiro, M; Duca, K A; Lee, K et al. (2008) A virtual look at Epstein-Barr virus infection: simulation mechanism. J Theor Biol 252:633-48

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