Abstract
This work brings nonlinear Beddington–DeAngelis immune expansion and virus stimulation delay into a classical immunosuppressive infection model developed by Komarova et al. (Proc Natl Acad Sci USA 100(4):1855–1860, 2003) to seek for the effective strategies in realizing the “functional cure” goal with sustained immunity. Compared with the classical model, stability analysis indicates that the nonlinear immune expansion brings about qualitative changes in dynamic features, and new immune control equilibrium appears even under the weak viral inhibitory effects. Global stability analysis for the model without delay shows that the unique local stable equilibrium is also globally asymptotically stable, and it just exhibits bistability dynamics and saddle-node bifurcation. While the virus stimulation delay induces plenty of complex dynamical features, including Hopf bifurcation, homoclinic, heteroclinic and singular closed orbits, sustained and transient oscillations. Numerical investigation reveals that a reduction in the two key parameters involved in the nonlinear immune expansion (i.e., immune competition intensity and virus inhibition intensity) can lengthen the bistable interval and expand the virus-control region, which enables the model to more readily stabilize at either an immune control equilibrium or a periodic orbit, achieving sustained immunity. Moreover, several strategies including the drug therapies targeted at the reduction in the two key parameters and the delay, could effectively shorten therapy duration, as well as the implementation of the weak intensity of therapy still can realize sustained immunity if the delay remains relatively small.
Similar content being viewed by others
References
Barber, D.L., Wherry, E.J., Masopust, D., Zhu, B., Allison, J.P., Sharpe, A.H., Freeman, G.L., Ahmed, R.: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439(7077), 682–687 (2006)
Wijaya, R.S., Read, S.A., Selvamani, S.P., Schibeci, S., Azardaryany, M.K., Ong, A., van der Poorten, D., Lin, R., Douglas, M.W., George, J., Ahlenstiel, G.: Hepatitis C virus eradication with interferon free, DAA-based therapy results in KLRG1+, hepatitis C virus-specific memory natural killer cells. J. Infect. Dis. 223(7), 1183–1195 (2021)
Davenport, M.P., Khoury, D.S., Cromer, D., Lewin, S.R., Kelleher, A.D., Kent, S.J.: Functional cure of HIV: the scale of the challenge. Nat. Rev. Immunol. 19(1), 45–54 (2019)
Meng, Z., Chen, Y., Lu, M.: Advances in targeting the innate and adaptive immune systems to cure chronic hepatitis B virus infection. Front. Immunol. 10, 3127 (2020)
Autran, B., Descours, B., Avettand-Fenoel, V., Rouzioux, C.: Elite controllers as a model of functional cure. Curr. Opin. HIV AIDS 6(3), 181–187 (2011)
Wagner, R., Randolph, J.T., Patel, S.V., et al.: Highlights of the structure-activity relationships of benzimidazole linked pyrrolidines leading to the discovery of the hepatitis C virus NS5A inhibitor pibrentasvir (ABT-530). J. Med. Chem. 61(9), 4052–4066 (2018)
Nath, B.J., Sarmah, H.K., Maurer, H.: An optimal control strategy for antiretroviral treatment of HIV infection in presence of immunotherapy. Qual. Theory. Dyn. Syst. 21(2), 1–26 (2022)
Sáez-Cirión, A., Bacchus, C., Hocqueloux, L., et al.: Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLOS. Pathog. 9(3), e1003211 (2013)
Deeks, S.G., Walker, B.D.: Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27(3), 406–416 (2007)
Browne, C.J., Smith, H.L.: Dynamics of virus and immune response in multi-epitope network. J. Math. Biol. 77(6), 1833–1870 (2018)
Prosperi, M.C.F., D’Autilia, R., Incardona, F., De Luca, A., Zazzi, M., Ulivi, G.: Stochastic modelling of genotypic drug-resistance for human immunodeficiency virus towards long-term combination therapy optimization. Bioinformatics 25(8), 1040–1047 (2009)
Rife Magalis, B., Autissier, P., Williams, K.C., Chen, X., Browne, C., Salemi, M.: Predator-prey Dynamics of intra-host simian immunodeficiency virus evolution within the untreated host. Front. Immunol. 12, 709962 (2021)
Komarova, N.L., Barnes, E., Klenerman, P., Wodarz, D.: Boosting immunity by antiviral drug therapy: a simple relationship among timing, efficacy, and success. Proc. Natl. Acad. Sci. USA 100(4), 1855–1860 (2003)
Wang, S., Xu, F.: Thresholds and bistability in virus-immune dynamics. Appl. Math. Lett. 78, 105–111 (2018)
Wang, S., Li, H., Xu, F.: Monotonic and nonmonotonic immune responses in viral infection systems. Discrete Contin. Dyn. Syst. Ser. B 27(1), 141–165 (2022)
Wang, S., Xu, F., Rong, L.: Bistability analysis of an HIV model with immune response. J. Biol. Syst. 25(4), 677–695 (2017)
Wang, S., Xu, F.: Analysis of an HIV model with post-treatment control. J. Appl. Anal. Comput. 10(2), 667–685 (2020)
Wodarz, D., Nowak, M.A.: Immune responses and viral phenotype: do replication rate and cytopathogenicity influence virus load? Comput. Math. Methods. Med. 2(2), 113–127 (2000)
De Boer, R.J.: Understanding the failure of CD8+ T-cell vaccination against simian/human immunodeficiency virus. J. Virol. 81(6), 2838–2848 (2007)
Wodarz, D.: Killer Cell Dynamics: Mathematical and Computational Approaches to Immunology. Springer, New York (2007)
De Boer, R.J., Perelson, A.S.: Towards a general function describing T cell proliferation. J. Theor. Biol. 175(4), 567–576 (1995)
De Boer, R.J., Perelson, A.S.: Target cell limited and immune control models of HIV infection: a comparison. J. Theor. Biol. 190(3), 201–214 (1998)
Beddington, J.R.: Mutual interference between parasites or predators and its effect on searching efficiency. J. Anim. Ecol. 44(1), 331–340 (1975)
Bairagi, N., Adak, D.: Dynamics of cytotoxic T-lymphocytes and helper cells in human immunodeficiency virus infection with Hill-type infection rate and sigmoidal CTL expansion. Chaos Solitons Fractals 103, 52–67 (2017)
Jiang, C., Wang, W.: Complete classification of global dynamics of a virus model with immune responses. Discrete Contin. Dyn. Syst. Ser. B 19(4), 1087 (2014)
Shu, H., Wang, L., Watmough, J.: Sustained and transient oscillations and chaos induced by delayed antiviral immune response in an immunosuppressive infection model. J. Math. Biol. 68(1), 477–503 (2014)
Shu, H., Wang, L.: Joint impacts of therapy duration, drug efficacy and time lag in immune expansion on immunity boosting by antiviral therapy. J. Biol. Syst. 25(1), 105–117 (2017)
Li, J., Ma, X., Li, J., Zhang, D.: Dynamics of a chronic virus infection model with viral stimulation delay. Appl. Math. Lett. 122, 107547 (2021)
Liu, Z., Wang, L., Tan, R.: Spatiotemporal dynamics for a diffusive HIV-1 infection model with distributed delays and CTL immune response. Discrete Contin. Dyn. Syst. Ser. B 27(5), 2767 (2022)
Chun, T.W., Stuyver, L., Mizell, S.B., Ehler, L.A., Mican, J.A.M., Baseler, M., Lloyd, A.L., Nowak, M.A., Fauci, A.S., Info, A.: Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 94(24), 13193–13197 (1997)
Lewin, S.R., Ribeiro, R.M., Walters, T., Lau, G.K., Bowden, S., Locarnini, S., Perelson, A.S.: Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed. Hepatology 34(5), 1012–1020 (2001)
Bekkering, F.C., Stalgis, C., McHutchison, J.G., Brouwer, J.T., Perelson, A.S.: Estimation of early hepatitis C viral clearance in patients receiving daily interferon and ribavirin therapy using a mathematical model. Hepatology 33(2), 419–423 (2001)
Johansen, P., Storni, T., Rettig, L., et al.: Antigen kinetics determines immune reactivity. Proc. Natl. Acad. Sci. USA 105(13), 5189–5194 (2008)
Nathanson, N.: Viral Pathogenesis and Immunity, 2nd edn. Academic Press, London (2008)
Perko, L.: Differential Equations and Dynamical Systems. Springer, New York (1991)
Conway, J.M., Perelson, A.S.: Post-treatment control of HIV infection. Proc. Natl. Acad. Sci. USA 112(17), 5467–5472 (2015)
Martcheva, M.: An Introduction to Mathematical Epidemiology. Springer, New York (2015)
Acknowledgements
This work is supported partially by National Natural Science Foundation of China (Nos. 12001178, 12271147) and Innovative Training Program for College Students of Hubei Minzu University (No. S202010517021).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Chen, Y., Wang, L., Liu, Z. et al. Complex Dynamics for an Immunosuppressive Infection Model with Virus Stimulation Delay and Nonlinear Immune Expansion. Qual. Theory Dyn. Syst. 22, 118 (2023). https://doi.org/10.1007/s12346-023-00814-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12346-023-00814-y