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MATHEMATICAL MODELING OF INTERLUEKIN-15 THERAPY FOR HUMAN IMMUNODEFICIENCY VIRUS

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posted on 2023-04-19, 21:13 authored by Jonathan William CodyJonathan William Cody

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.

Funding

Indiana Center for AIDS Research [www.niaid.nih.gov/research/centers-aidsresearch]

Characterizing the mechanism of post-treatment control of SIV in Mauritian cynomolgus macaques

National Institute of Allergy and Infectious Diseases

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History

Degree Type

  • Doctor of Philosophy

Department

  • Biomedical Engineering

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Elsje Pienaar

Additional Committee Member 2

Tamara L. Kinzer-Ursem

Additional Committee Member 3

Nan Kong

Additional Committee Member 4

David Umulis

Additional Committee Member 5

Shelby L. O’Connor