1. Mathematical modeling of N-803 treatment in SIV-infected non-human primates
- Author
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Amy L. Ellis-Connell, Jonathan W. Cody, Shelby L. O’Connor, and Elsje Pienaar
- Subjects
RNA viruses ,0301 basic medicine ,Physiology ,viruses ,Lymphocyte ,Cell ,Simian Acquired Immunodeficiency Syndrome ,NK cells ,CD8-Positive T-Lymphocytes ,Virus Replication ,Pathology and Laboratory Medicine ,medicine.disease_cause ,0302 clinical medicine ,Immunodeficiency Viruses ,Drug tolerance ,Cellular types ,Cytotoxic T cell ,Biology (General) ,Interleukin-15 ,Ecology ,Pharmaceutics ,Immune cells ,Viral Load ,Body Fluids ,Killer Cells, Natural ,Blood ,medicine.anatomical_structure ,SIV ,Computational Theory and Mathematics ,Medical Microbiology ,Viral Pathogens ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Viruses ,White blood cells ,Simian Immunodeficiency Virus ,Pathogens ,Anatomy ,Viral load ,Research Article ,Cell biology ,Blood cells ,Drug Research and Development ,QH301-705.5 ,Recombinant Fusion Proteins ,T cell ,Immunology ,T cells ,Cytotoxic T cells ,Biology ,Models, Biological ,Microbiology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,Drug Therapy ,Virology ,Retroviruses ,Immune Tolerance ,Genetics ,medicine ,Animals ,Humans ,Microbial Pathogens ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Drug Regulation ,Medicine and health sciences ,Pharmacology ,Biology and life sciences ,Lentivirus ,Organisms ,Computational Biology ,Mathematical Concepts ,Simian immunodeficiency virus ,Macaca mulatta ,030104 developmental biology ,Animal cells ,Viral Transmission and Infection ,CD8 - Abstract
Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N-803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies., Author summary Immune therapy may be a critical component in the functional cure for Human Immunodeficiency Virus (HIV). N-803 is an immunotherapeutic drug that activates antigen-specific CD8+ T cells of the immune system. These CD8+ T cells eliminate HIV-infected cells in order to limit the spread of infection in the body. In one study, N-803 reduced plasma viremia in macaques that were infected with Simian Immunodeficiency Virus, an analog of HIV. Here, we used mathematical models to analyze the data from this study to better understand the effects of N-803 therapy on the immune system. Our models indicated that inhibitory signals may be reversing the stimulatory effect of N-803. Results also suggested the possibilities that tolerance to N-803 could build up within the CD8+ T cells themselves and that the treatment may be selecting for virus strains that are not targeted by CD8+ T cells. Our models predict that N-803 therapy may be made more effective if the time between doses is increased or if inhibitory signals are blocked by an additional drug. Also, N-803 may need to be combined with other immune therapies to target virus that would otherwise evade CD8+ T cells.
- Published
- 2020