Abstract
Epstein–Barr virus (EBV) infects and can persist in a majority of people worldwide. Within an infected host, EBV targets two major cell types, B cells and epithelial cells, and viruses emerging from one cell type preferentially infect the other. We use mathematical models to understand why EBV infects epithelial cells when B cells serve as a stable refuge for the virus and how switching between infecting each cell type affects virus persistence and shedding. We propose a mathematical model to describe the regulation of EBV infection within a host. This model is used to study the effects of parameter values on optimal viral strategies for transmission, persistence, and intrahost competition. Most often, the optimal strategy to maximize transmission is for viruses to infect epithelial cells, but the optimal strategy for maximizing intrahost competition is for viruses to mainly infect B cells. Applying the results of the within-host model, we derive a model of EBV dynamics in a homogeneous population of hosts that includes superinfection. We use this model to study the conditions necessary for invasion and coexistence of various viral strategies at the population level. When the importance of intrahost competition is weak, we show that coexistence of different strategies is possible.
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References
Adler, F. R., & Mosquera, J. (2000). Is space necessary? Interference competition and limits to biodiversity. Ecology, 81(11), 3226–3232.
Andiman, W. A. (2006). Epidemiology of primary Epstein–Barr virus infection and infectious mononucleosis. In A. Tselis & H. B. Jenson (Eds.), Epstein–Barr virus (Vol. 1, 1st ed., pp. 39–57). New York: Taylor & Francis.
Borza, C. M., & Hutt-Fletcher, L. M. (2002). Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus. Nat. Med., 8(6), 594–599.
Borza, C. M., Morgan, A. J., Turk, S. M., & Hutt-Fletcher, L. M. (2004). Use of gHgL for attachment of Epstein–Barr virus to epithelial cells compromises infection. J. Virol., 7(10), 5007–5014.
Bremermann, H. J., & Thieme, H. R. (1989). A competitive exclusion principle for pathogen virulence. J. Math. Biol., 27(2), 179–190.
Castiglione, F., Duca, K., Jarrah, A., Laubenbacher, R., Hochberg, D., & Thorley-Lawson, D. A. (2007). Simulating Epstein–Barr virus infection with C-ImmSim. Bioinformatics, 23(11), 1371–1377.
Davenport, M., Fazou, C., McMichael, A. J., & Callan, M. F. C. (2002). Clonal selection, clonal senescence, and clonal succession: the evolution of the T cell response to infection with a persistent virus. J. Immunol., 168(7), 3309–3317.
Haan, K. M., Kwok, W. W., Longnecker, R., & Speck, P. (2000). Epstein–Barr virus entry utilizing HLA-DP or HLA-DQ as a coreceptor. J. Virol., 74(5), 2451–2454.
Heffernan, J. M., Smith, R. J., & Wahl, L. M. (2005). Perspectives on the basic reproductive ratio. J. R. Soc. Interface, 2(4), 281–293.
Hislop, A. D., Taylor, G. S., Sauce, D., & Rickinson, A. B. (2007). Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu. Rev. Immunol., 25(1), 587–617.
Hutt-Fletcher, L. M. (2005). EBV entry and epithelial infection. In E. S. Robertson (Ed.), Epstein–Barr virus (Vol. 1, 1st ed., pp. 359–378). Norfolk: Caister Academic Press.
Hutt-Fletcher, L. M. (2007). Epstein–Barr virus entry. J. Virol., 81(15), 7825–7832.
Jiang, R., Scott, R. S., & Hutt-Fletcher, L. M. (2006). Epstein–Barr virus shed in saliva is high in B-cell-tropic gp42. J. Virol., 80(14), 7281–7283.
Jones, L., & Perelson, A. (2005). Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART. Bull. Math. Biol., 67(6), 1227–1251.
Macallan, D. C., Wallace, D. L., Zhang, Y., Ghattas, H., Asquith, B., Lara, C., Worth, A., Panayiotakopoulos, G., Griffin, G. E., Tough, D. F., & Beverley, P. C. (2005). B-cell kinetics in humans: rapid turnover of peripheral blood memory cells. Blood, 105(9), 3633–3640.
Mocarski, E. S., Shenk, T., & Pass, R. F. (2007). Cytomegaloviruses. In D. M. Knipe & P. M. Howley (Eds.), Field’s virol (Vol. 2, 5th ed., pp. 2701–2772). Philadelphia: Williams & Wilkins.
Mosquera, J., & Adler, F. R. (1998). Evolution of virulence: a unified framework for coinfection and superinfection. J. Theor. Biol., 195(3), 293–313.
Rickinson, A., & Kieff, E. (2001). Epstein-Barr Virus. In D. M. Knipe & P. M. Howley (Eds.), Field’s virol (Vol. 2, 4th ed., pp. 2575–2627). Philadelphia: Williams & Wilkins.
Robertson, E. S. (Ed.) (2005). Epstein-Barr virus (Vol. 1, 1st ed.). Norfolk: Caister Academic Press.
Shapiro, M., Duca, K. A., Lee, K., Delgado-Eckert, E., Hawlins, J., Jarrah, A. S., Laubenbacher, R., Laubenbacher, R., Polys, N. F., Hadinoto, V., & Thorley-Lawson, D. A. (2008). A virtual look at Epstein–Barr virus infection: Simulation mechanism. J. Theor. Biol., 252(4), 633–648.
Sitki-Green, D., Covington, M., & Raab-Traubb, N. (2003). Compartmentalization and transmission of multiple Epstein–Barr virus strains in asymptomatic carriers. J. Virol., 77(3), 1840–1847.
Sixbey, J. W., & Yao, Q. Y. (1992). Immunoglobulin A-induced shift of Epstein–Barr virus tissue tropism. Science, 255(5051), 1578–1580.
Thorley-Lawson, D. A. (2005). EBV persistence and latent infection in vivo. In E. S. Robertson (Ed.), Epstein–Barr virus (Vol. 1, 1st ed., pp. 309–349). Norfolk: Caister Academic Press.
Turk, S. M., Jiang, R., Chesnokova, L. S., & Hutt-Fletcher, L. M. (2006). Antibodies to gp350/220 enhance the ability of Epstein-Barr virus to infect epithelial cells. J. Virol., 80(19), 9628–9633.
van den Driessche, P., & Watmough, J. (2002). Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission. Math. Biosci., 180(1–2), 29–48.
Wang, G., Krueger, G. R. F., & Buje, L. M. (2003). Mathematical model to simulate the cellular dynamics of infection with human herpesvirus-6 in EBV-negative infectious mononucleosis. J. Med. Virol., 71(4), 569–577.
Wodarz, D., Sierro, S., & Klenerman, P. (2007). Dynamics of killer T cell inflation in viral infections. J. R. Soc. Interface, 4(14), 533–543.
Yamanishi, K., Mori, Y., & Pellett, P. E. (2007). Human herpesviruses 6 and 7. In D. M. Knipe & P. M. Howley (Eds.), Field’s virol (Vol. 2, 5th ed., pp. 2701–2772). Philadelphia: Williams & Wilkins.
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Huynh, G.T., Adler, F.R. Alternating Host Cell Tropism Shapes the Persistence, Evolution and Coexistence of Epstein–Barr Virus Infections in Human. Bull Math Biol 73, 1754–1773 (2011). https://doi.org/10.1007/s11538-010-9590-8
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DOI: https://doi.org/10.1007/s11538-010-9590-8