title: On the Role of CD8+T Cells in Determining Recovery Time from Influenza Virus Infection.
abstract: Myriad experiments have identified an important role for CD8+T cell response mechanisms in determining recovery from influenza A virus infection. Animal models of influenza infection further implicate multiple elements of the immune response in defining the dynamical characteristics of viral infection. To date, influenza virus models, while capturing particular aspects of the natural infection history, have been unable to reproduce the full gamut of observed viral kinetic behavior in a single coherent framework. Here, we introduce a mathematical model of influenza viral dynamics incorporating innate, humoral, and cellular immune components and explore its properties with a particular emphasis on the role of cellular immunity. Calibrated against a range of murine data, our model is capable of recapitulating observed viral kinetics from a multitude of experiments. Importantly, the model predicts a robust exponential relationship between the level of effector CD8+T cells and recovery time, whereby recovery time rapidly decreases to a fixed minimum recovery time with an increasing level of effector CD8+T cells. We find support for this relationship in recent clinical data from influenza A (H7N9) hospitalized patients. The exponential relationship implies that people with a lower level of naive CD8+T cells may receive significantly more benefit from induction of additional effector CD8+T cells arising from immunological memory, itself established through either previous viral infection or T cell-based vaccines.
authors.affiliation: School of Mathematics and Statistics, The University of Melbourne , Melbourne, VIC , Australia.
authors.forename: Pengxing
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia; Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Mathematics and Statistics, The University of Melbourne , Melbourne, VIC , Australia.
authors.forename: Ada W C
authors.initials: AW
authors.lastname: Yan
authors.affiliation: Doherty Epidemiology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Modelling and Simulation, Infection and Immunity Theme, Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Jodie
authors.initials: J
authors.lastname: McVernon
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Institutes of Biomedical Sciences, Fudan University , Shanghai , China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Modelling Infection and Immunity Lab, Centre for Disease Modelling, York Institute for Health Research, Mathematics and Statistics, York University , Toronto, ON , Canada.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Heffernan
authors.affiliation: Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital , Melbourne, VIC , Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.affiliation: School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Modelling and Simulation, Infection and Immunity Theme, Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: James M
authors.initials: JM
authors.lastname: McCaw
keywords: cellular immunity; influenza; mathematical model; recovery time; viral dynamics