BME PhD Defense Announcement for Jonathan Cody (E. Pienaar, advisor) Everyone is invited to attend the public presentation beginning at 1:30 PM. Title: “Mathematical Modeling of Interluekin-15 Therapy for Human Immunodeficiency Virus” Time: Tuesday, April 4th from 1:30-3:30 PM Place: Hall for Discovery and Learning Research DLR 131 and on Zoom https://purdue-edu.zoom.us/j/94454650628?pwd=ZnFUWkJCSXFtSER4VlVPS2xqeVlJQT0... Committee: Elsje Pienaar (Major Professor), Tamara Kinzer-Ursem, Nan Kong, Shelby O’Connor, David Umulis Abstract: Interleukin-15 (IL-15) is a cytokine that promotes maintenance and activation of cytotoxic immune cells. Therapeutic IL-15 stimulates these cells to fight cancer and chronic infections, such as Human Immunodeficiency Virus (HIV). Animal models of HIV have demonstrated that IL-15 agonists can suppress the virus, but this was transient and was not observed in all cohorts. We developed a mechanistic mathematical model of IL-15 therapy of HIV to explain these differences in efficacy and to explore solutions. First, the model was applied to evaluate mitigating factors, including immune regulation, viral escape, and drug tolerance, using Akaike Information Criterion. We found that immune regulatory mechanisms could explain the viral rebound observed with continued IL-15 therapy. Next, the model was expanded to allow it to simultaneously explain both the transient viral suppression noted above and the lack of viral suppression observed in another animal cohort. In this cohort, the model suggested that higher pre-treatment viral load came with higher activation of immune cells and a balancing regulatory inhibition of cytotoxicity. Finally, we conducted stability analysis at a range of IL-15 therapeutic strengths. While there was an ideal IL-15 strength, monotherapy could not maintain viral levels below what would clinically be considered to be safely controlled. Stable viral control in the model required the combination of IL-15 with blockade of key regulatory pathways. Immune therapy of complex diseases will likely require combinations of medicines that boost the immune response at multiple key points. Mathematical models like this can expedite development of these treatments.