Modeling the Kinetics of EBV in Primary Carriers and Transplant Recipeints

• Author / Creator

  Akinwumi, Segun M

• Epstein-Barr virus (EBV) is a “kissing disease virus” that has infected more than 95% of the adult human population. It has been associated with diseases such as Acute Infectious Mononucleosis (AIM) and post-transplant lymphoproliferative disorder (PTLD). The kinetics of primary EBV infection has a profound impact on the viral persistence and elements of the kinetic profile have been associated with risk factor for the development of PTLD. In the setting of organ transplantation, optimising immunosuppressive therapy remains difficult because preventing rejection must be balanced against the risk of infection and malignancy. Our knowledge of how immunosuppression affects quantitative levels of EBV-infected cells in transplant recipients is limited. We developed a mathematical model of primary EBV infection based on the biological process of EBV infection of B cells and immune responses to EBV based on the theoretical model of EBV biology known as the germinal center model. We used the model to investigate the impacts of immunosuppression on EBV kinetics in transplant settings by coupling the mathematical model of EBV infection with mathematical models of drugs used to mitigate organ rejection in transplant recipients. The model was able to reproduce patterns of the kinetics of EBV infection observed in clinical data. Our model analysis showed that the rate of EBV infection of naïve B cells, the proliferation rate of infected B cells in the germinal center, and the activation rate of EBV specific cytotoxic lymphocytes (CTL) are key model parameters that strongly influence kinetics of primary EBV infection. The innoculation size of the EBV affects the peak value of EBV memory B cells and the time to peak. Antiviral treatments of duration 3-6 months have little effect on the EBV-infected memory B cell load, and a perfect antiviral agent applied long-term can clear EBV in this compartment in three years. Antithymocyte globulin appeared to increase both peak and set point in the memory B cell compartment when combined with maintenance immunosuppression alone in contrast to the use of basiliximab. We observed higher peak, longer time to peak, longer time to setpoint, and higher setpoint for infected memory B cells and EBV with antithymocyte globulin combined with maintenance immunosuppression alone compared to the use of basiliximab combined with maintenance immunosuppression. Antiviral treatment given at the time of transplant for period of 3-6 months appeared to reduce peak viral load when combined with either antithymocyte globulin or basiliximab and maintenance immunosuppression.

• Subjects / Keywords

  • Valganciclovir
  • Basliximab
  • Mathematical Modeling
  • EBV
  • Antithymocyte globulin
  • Rituximab
  • PTLD
  • Immunology
  • Epidemiology
  • AIM
  • Transplantation
  • Immunosuppressive Drugs

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3HH6CK80

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.