Mathematical Models of Programmed CTL Proliferation

Summary

Principal Investigator: DOMINIK F WODARZ
Abstract: Previous mathematical models of CTL responses assumed that CTL expansion required continuous antigenic stimulation. Recent experiments have shown, however, that a single encounter with antigen can send CTL into a program of proliferation and differentiation. Execution of the program does not require further antigenic stimulation, and leads to the generation of effector and memory CTL. The proposal aims to construct and analyze mathematical models which describe the process of programmed CTL proliferation, and to couple the modeling work with experimental studies through a specific collaboration. The basic mathematical model will be validated with data from VSV infected mice, and this will involve the measurement of crucial parameters. It will be compared how the programmed proliferation model differs from the continuous stimulation models which have been used so far. Are the results from the continuous stimulation models obsolete or do they remain robust? Why has programmed proliferation evolved? After this general analysis two specific aspects of CTL dynamics will be investigated in the context of programmed proliferation. These are the role of effector molecules (such as perform and IFN-g) for CTL dynamics, and the role of CD4 T cell help. The modeling work will be complemented by experiments with VSV and LCMV infected mice.
Funding Period: 2005-07-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America
    PLoS Comput Biol 8:e1002547. 2012
  2. ncbi Multiple HIV-1 infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology and Department of Mathematics, 321 Steinhaus Hall, University of California, Irvine, California 92697, USA
    Evolution 63:2326-39. 2009
  3. pmc ODE models for oncolytic virus dynamics
    Natalia L Komarova
    Department of Mathematics, 340 Rowland Hall, University of California, Irvine, CA 92697, USA
    J Theor Biol 263:530-43. 2010
  4. ncbi The worst drug rule revisited: mathematical modeling of cyclic cancer treatments
    Allen A Katouli
    Department of Mathematics, University of California Irvine, Irvine, CA 92697, USA
    Bull Math Biol 73:549-84. 2011
  5. pmc Effect of different modes of viral spread on the dynamics of multiply infected cells in human immunodeficiency virus infection
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, 321 Steinhaus Hall, Irvine, CA 92697, USA
    J R Soc Interface 8:289-300. 2011
  6. ncbi Mathematical modeling of cyclic treatments of chronic myeloid leukemia
    Natalia L Komarova
    Department of Mathematics, University of California Irvine, Irvine CA 92697, United States
    Math Biosci Eng 8:289-306. 2011
  7. ncbi Effect of multiple infection of cells on the evolutionary dynamics of HIV in vivo: implications for host adaptation mechanisms
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Exp Biol Med (Maywood) 236:926-37. 2011
  8. pmc Towards predictive computational models of oncolytic virus therapy: basis for experimental validation and model selection
    Dominik Wodarz
    Department of Ecology and Evolution, University of California Irvine, Irvine, California, United States of America
    PLoS ONE 4:e4271. 2009
  9. pmc Immunity and protection by live attenuated HIV/SIV vaccines
    Dominik Wodarz
    Department of Ecology and Evolution, 321 Steinhaus Hall, University of California, Irvine CA 92697, USA
    Virology 378:299-305. 2008
  10. ncbi Viral reproductive strategies: How can lytic viruses be evolutionarily competitive?
    Natalia L Komarova
    Department of Mathematics, University of California, Irvine, CA 92697, USA
    J Theor Biol 249:766-84. 2007

Detail Information

Publications23

  1. pmc Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, Irvine, California, United States of America
    PLoS Comput Biol 8:e1002547. 2012
    ..This analysis provides a first step towards understanding spatial oncolytic virus dynamics, upon which more detailed investigations and further complexity can be built...
  2. ncbi Multiple HIV-1 infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology and Department of Mathematics, 321 Steinhaus Hall, University of California, Irvine, California 92697, USA
    Evolution 63:2326-39. 2009
    ..It is hypothesized that an intermediate strength of the CTL response, and thus the suboptimal virus suppression observed in HIV-1 infection, might be adaptive to minimize the impact of existing CTL escape mutants on overall virus load...
  3. pmc ODE models for oncolytic virus dynamics
    Natalia L Komarova
    Department of Mathematics, 340 Rowland Hall, University of California, Irvine, CA 92697, USA
    J Theor Biol 263:530-43. 2010
    ..Our methodology can be used to study the dynamics of many biological systems, and thus has implications beyond the study of virus therapy of cancers...
  4. ncbi The worst drug rule revisited: mathematical modeling of cyclic cancer treatments
    Allen A Katouli
    Department of Mathematics, University of California Irvine, Irvine, CA 92697, USA
    Bull Math Biol 73:549-84. 2011
    ..The connection with the "worst drug rule" of Day (Cancer Res. 46:3876, 1986b) is discussed...
  5. pmc Effect of different modes of viral spread on the dynamics of multiply infected cells in human immunodeficiency virus infection
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, 321 Steinhaus Hall, Irvine, CA 92697, USA
    J R Soc Interface 8:289-300. 2011
    ....
  6. ncbi Mathematical modeling of cyclic treatments of chronic myeloid leukemia
    Natalia L Komarova
    Department of Mathematics, University of California Irvine, Irvine CA 92697, United States
    Math Biosci Eng 8:289-306. 2011
    ..We further investigate the situation where a degree of cross-resistance is present, such that certain mutations cause cells to become resistant to both drugs simultaneously...
  7. ncbi Effect of multiple infection of cells on the evolutionary dynamics of HIV in vivo: implications for host adaptation mechanisms
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Exp Biol Med (Maywood) 236:926-37. 2011
    ..Here, we review this topic and discuss how immune control of the infection and the ability of the virus to escape immune control is affected by co-infection...
  8. pmc Towards predictive computational models of oncolytic virus therapy: basis for experimental validation and model selection
    Dominik Wodarz
    Department of Ecology and Evolution, University of California Irvine, Irvine, California, United States of America
    PLoS ONE 4:e4271. 2009
    ..It can further serve as the basis for future, more complex models that take into account other clinically relevant factors such as immune responses...
  9. pmc Immunity and protection by live attenuated HIV/SIV vaccines
    Dominik Wodarz
    Department of Ecology and Evolution, 321 Steinhaus Hall, University of California, Irvine CA 92697, USA
    Virology 378:299-305. 2008
    ..According to these arguments, an inverse correlation between the level of attenuation and the level of protection is expected, and this has indeed been observed in experimental data...
  10. ncbi Viral reproductive strategies: How can lytic viruses be evolutionarily competitive?
    Natalia L Komarova
    Department of Mathematics, University of California, Irvine, CA 92697, USA
    J Theor Biol 249:766-84. 2007
    ..Similarly, there is an evolutionary pressure to extend the life-span as a response to antibody action...
  11. pmc Effect of cellular quiescence on the success of targeted CML therapy
    Natalia L Komarova
    Department of Mathematics, University of California Irvine, Irvine, California, United States of America
    PLoS ONE 2:e990. 2007
    ..Using mathematical models, we investigate the effect of cellular quiescence on the outcome of therapy with targeted small molecule inhibitors...
  12. pmc Human immunodeficiency virus evolution towards reduced replicative fitness in vivo and the development of AIDS
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, 321 Steinhaus Hall, Irvine, CA 92697, USA
    Proc Biol Sci 274:2481-90. 2007
    ....
  13. ncbi The fixed-size Luria-Delbruck model with a nonzero death rate
    Natalia L Komarova
    Department of Mathematics, University of California, Irvine, CA 92697, United States
    Math Biosci 210:253-90. 2007
    ..Finally, we investigate the applicability of the traditional, 'fixed-time' approach and find that it approximates the 'fixed-size' problem whenever stochastic effects are negligible...
  14. ncbi Stochastic modeling of drug resistance in cancer
    Natalia Komarova
    Department of Mathematics and Ecology and Evolution, University of California, Irvine, CA 92697, USA
    J Theor Biol 239:351-66. 2006
    ..For very high-turnover rates, increasing the number of drugs used does not significantly increase the chances of treatment success...
  15. ncbi Ecological and evolutionary principles in immunology
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Ecol Lett 9:694-705. 2006
    ....
  16. pmc Model-driven approaches for in vitro combination therapy using ONYX-015 replicating oncolytic adenovirus
    Ryan Zurakowski
    Department of Electrical and Computer Engineering, 140 Evans Hall, University of Delaware, Newark, DE 19716, USA
    J Theor Biol 245:1-8. 2007
    ..We introduce a mathematical model of these dynamics and show simple optimal control based strategies which motivate this approach...
  17. pmc Dynamics of killer T cell inflation in viral infections
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697, USA
    J R Soc Interface 4:533-43. 2007
    ..This model provides valuable information and may help to explain the inflation of CMV specific CD8+T cells seen in humans as they age...
  18. pmc Mathematical models of specificity in cell signaling
    Lee Bardwell
    Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697 2300, USA
    Biophys J 92:3425-41. 2007
    ..The effects of noise are also examined. The insights gained from this analysis are applied to understanding specificity in the yeast mating and invasive growth MAP kinase signaling network...
  19. pmc Infection dynamics in HIV-specific CD4 T cells: does a CD4 T cell boost benefit the host or the virus?
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Math Biosci 209:14-29. 2007
    ....
  20. ncbi Can loss of apoptosis protect against cancer?
    Dominik Wodarz
    Department of Ecology and Evolution, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Trends Genet 23:232-7. 2007
    ....
  21. pmc On the relative fitness of early and late stage Simian immunodeficiency virus isolates
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Theor Popul Biol 72:426-35. 2007
    ..One possibility is that the ability of multiple virus particles to infect the same cell (coinfection) might be a pre-requisite for the emergence of the cytopathic strain SIVMne170 as the disease progresses...
  22. pmc Selective pressures for and against genetic instability in cancer: a time-dependent problem
    Natalia L Komarova
    Department of Mathematics, University of California, Irvine, CA 92697, USA
    J R Soc Interface 5:105-21. 2008
    ..We also identify parameter regimes where it is advantageous to keep stable (or unstable) constantly throughout the growth...
  23. ncbi Effect of the CTL proliferation program on virus dynamics
    Dominik Wodarz
    Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
    Int Immunol 17:1269-76. 2005
    ..We discuss these results in the context of data from murine virus infections and explore implications for virus dynamics in CD4 helper-deficient hosts...