Skip to main content
Log in

Impacts of the Cell-Free and Cell-to-Cell Infection Modes on Viral Dynamics

  • Published:
Journal of Dynamics and Differential Equations Aims and scope Submit manuscript

Abstract

Virus can disseminate between uninfected target cells via two modes, namely, the diffusion-limited cell-free viral spread and the direct cell-to-cell transfer using virological synapses. To examine how these two viral infection modes impact the viral dynamics, in this paper, we propose and analyze a general viral infection model that incorporates these two viral infection modes. The model also includes nonlinear target-cell dynamics, infinitely distributed intracellular delays, nonlinear incidences, and concentration-dependent clearance rates. It is shown that the numbers of secondly infected cells through the cell-free infection mode and the cell-to-cell infection mode both contribute to the basic reproduction number. Under some reasonable assumptions, the model exhibits a global threshold dynamics: the infection is cleared out if the basic reproduction number is less than one and the infection persists if the basic reproduction number is larger than one. Two specific examples are provided to illustrate that our theoretical results cover and improve some existing ones. When the underlying assumptions are not satisfied, oscillations via global Hopf bifurcation can be observed. A brief simulation of two-parameter bifurcation analysis is given to explore the joint impacts on viral dynamics for the interplay between nonlinear target-cell dynamics and intracellular delays.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Atkinson, F.V., Haddock, J.R.: On determining phase spaces for functional differential equations. Funkc. Ekvac 31, 331–347 (1988)

    MathSciNet  MATH  Google Scholar 

  2. Burton, T., Hutson, V.: Repellers in systems with infinite delay. J. Math. Anal. Appl. 137, 240–263 (1989)

    Article  MathSciNet  Google Scholar 

  3. Culshaw, R.V., Ruan, S., Webb, G.: A mathematical model of cell-to-cell spread of HIV-1 that includes a time delay. J. Math. Biol. 46, 425–444 (2003)

    Article  MathSciNet  Google Scholar 

  4. De Leenheer, P., Smith, H.L.: Virus dynamics: a global analysis. SIAM J. Appl. Math. 63, 1313–1327 (2003)

    Article  MathSciNet  Google Scholar 

  5. Diekmann, O., Heesterbeek, J.A.P., Metz, J.A.J.: On the definition and the computation of the basic reproduction ratio \(R_0\) in models for infectious diseases in heterogeneous populations. J. Math. Biol. 28, 365–382 (1990)

    Article  MathSciNet  Google Scholar 

  6. Dixit, N.M., Markowitz, M., Ho, D.D., Perelson, A.S.: Estimates of intracellular delay and average drug efficacy from viral load data of HIV-infected individuals under antiretroviral therapy. Antivir. Ther. 9, 237–246 (2004)

    Google Scholar 

  7. Engelborghs, K., Luzyanina, T., Samaey, G.: DDE-BIFTOOL v. 2.00: a Matlab package for bifurcation analysis of delay differential equations. Technical Report TW-330, University of Leuven, Belgium (2001)

  8. Erbe, L.H., Krawcewicz, W., Geba, K., Wu, J.: \(S^{1}\)-degree and global Hopf bifurcation theory of functional differential equations. J. Differ. Equ. 98, 198–277 (1992)

  9. Galloway, N.L.K., Doitsh, G., Monroe, K.M., Yang, Z., Muñoz-Arias, I., Levy, D.N., Greene, W.C.: Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of lymphoid-tissue-derived CD4 T cells. Cell Rep. 12, 1555–1563 (2015)

    Article  Google Scholar 

  10. Guckenheimer, J., Holmes, P.: Nonlinear Oscillations, Dynamical Systems, and Bifurcations of Vector Fields. Springer, New York (1983)

    Book  Google Scholar 

  11. Hale, J.K., Kato, J.: Phase space for retarded equations with infinite delay. Funkc. Ekvac 21, 11–41 (1978)

    MathSciNet  MATH  Google Scholar 

  12. Hale, J.K., Verduyn Lunel, S.M.: Introduction to Functional Differential Equations. Springer, New York (1993)

    Book  Google Scholar 

  13. Hale, J.K., Waltman, P.: Persistence in infinite-dimensional systems. SIAM J. Math. Anal. 20, 388–395 (1989)

    Article  MathSciNet  Google Scholar 

  14. Herz, V., Bonhoeffer, S., Anderson, R., May, R., Nowak, M.: Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay. Proc. Natl. Acad. Sci. USA 93, 7247–7251 (1996)

    Article  Google Scholar 

  15. Hino, Y., Murakami, S., Naito, T.: Functional-differential equations with infinite delay. Lecture Notes in Math, vol. 1473. Springer, Berlin (1991)

  16. Huang, G., Takeuchi, Y., Ma, W.: Lyapunov functional for delay differential equations model of viral infections. SIAM J. Appl. Math. 70, 2693–2708 (2010)

    Article  MathSciNet  Google Scholar 

  17. Hübner, W., McNerney, G.P., Chen, P., Dale, B.M., Gordan, R.E., Chuang, F.Y.S., Li, X.D., Asmuth, D.M., Huser, T., Chen, B.K.: Quantitative 3D video microscopy of HIV transfer across T cell virological synapses. Science 323, 1743–1747 (2009)

    Article  Google Scholar 

  18. Iwami, S., Takeuchi, J.S., Nakaoka, S., Mammano, F., Clavel, F., Inaba, H., Kobayashi, T., Misawa, N., Aihara, K., Koyanagi, Y., Sato, K.: Cell-to-cell infection by HIV contributes over half of virus infection. eLife (2015). doi:10.7554/eLife. 08150

  19. Jolly, C., Sattentau, Q.: Retroviral spread by induction of virological synapses. Traffic 5, 643–650 (2004)

    Article  Google Scholar 

  20. Komarova, N.L., Anghelina, D., Voznesensky, I., Trinite, B., Levy, D.N., Wodarz, D.: Relative contribution of free-virus and synaptic transmission to the spread of HIV-1 through target cell populations. Biol. Lett. 9, 1049–1055 (2012)

    Article  Google Scholar 

  21. Komarova, N.L., Wodarz, D.: Virus dynamics in the presence of synaptic transmission. Math. Biosci. 242, 161–171 (2013)

    Article  MathSciNet  Google Scholar 

  22. Komarova, N.L., Levy, D.N., Wodarz, D.: Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs. Sci. Rep. 3, 1–8 (2013)

    Article  Google Scholar 

  23. Kouche, M., Ainseba, B.: A mathematical model of HIV-1 infection including the saturation erffect of healthy cell proliferation. Int. J. Appl. Math. Comput. Sci. 20, 601–612 (2010)

    Article  MathSciNet  Google Scholar 

  24. Kuang, Y.: Delay Differential Equations with Applications in Population Biology. Academic Press, San Diego (1993)

    MATH  Google Scholar 

  25. Lai, X., Zou, X.: Modelling HIV-1 virus dynamics with both virus-to-cell infection and cell-to-cell transmission. SIAM J. Appl. Math. 74, 898–917 (2014)

    Article  MathSciNet  Google Scholar 

  26. Lai, X., Zou, X.: Modeling cell-to-cell spread of HIV-1 with logistic target cell growth. J. Math. Anal. Appl. 426, 563–584 (2015)

    Article  MathSciNet  Google Scholar 

  27. Lehmann, M., Nikolic, D.S., Piguet, V.: How HIV-1 takes advantage of the cytoskeleton during replication and cell-to-cell transmission. Viruses 3, 1757–1776 (2011)

    Article  Google Scholar 

  28. Li, F., Wang, J.: Analysis of an HIV infection model with logistic target-cell growth and cell-to-cell transmission. Chaos Solitons Fractals 81, 136–145 (2015)

    Article  MathSciNet  Google Scholar 

  29. Li, M.Y., Shu, H.: Impact of intracellular delays and target-cell dynamics on in vivo viral infections. SIAM J. Appl. Math. 70, 2434–2448 (2010)

    Article  MathSciNet  Google Scholar 

  30. Martin, N., Sattentau, Q.: Cell-to-cell HIV-1 spread and its implications for immune evasion. Curr. Opin. HIV AIDS 4, 143–149 (2009)

    Article  Google Scholar 

  31. McCluskey, C.C.: Global stability for an SEIR epidemiological model with varying infectivity and infinite delay. Math. Biosci. Eng. 6, 603–610 (2009)

    Article  MathSciNet  Google Scholar 

  32. McCluskey, C.C.: Complete global stability for an SIR epidemic model with delaydistributed or discrete. Nonlinear Anal. Real World Appl. 11, 55–59 (2010)

    Article  MathSciNet  Google Scholar 

  33. Murase, A., Sasaki, T., Kajiwara, T.: Stability analysis of pathogen-immune interaction dynamics. J. Math. Biol. 51, 247–267 (2005)

    Article  MathSciNet  Google Scholar 

  34. Nelson, P.W., Perelson, A.S.: Mathematical analysis of delay differential equation models of HIV-1 infection. Math. Biosci. 179, 73–94 (2002)

    Article  MathSciNet  Google Scholar 

  35. Nowak, M.A., Bangham, C.R.M.: Population dynamics of immune responses to persistent viruses. Science 272, 74–79 (1996)

    Article  Google Scholar 

  36. Nowak, M.A., Bonhoeffer, S., Hill, A.M., Boehme, R., Thomas, H.C.: Viral dynamics in hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 93, 4398–4402 (1996)

    Article  Google Scholar 

  37. Perelson, A.S., Nelson, P.W.: Mathematical analysis of HIV-1 dynamics in vivo. SIAM Rev. 41, 3–44 (1999)

    Article  MathSciNet  Google Scholar 

  38. Phillips, D.M.: The role of cell-to-cell transmission in HIV infection. AIDS 8, 719–731 (1994)

    Article  Google Scholar 

  39. Pourbashash, H., Pilyugin, S.S., De Leenheer, P., McCluskey, C.: Global analysis of within host virus models with cell-to-cell viral transmission. Discrete Contin. Dyn. Syst. Ser. B 19, 3341–3357 (2014)

    Article  MathSciNet  Google Scholar 

  40. Röst, G., Wu, J.: SEIR epidemiological model with varying infectivity and infinite delay. Math. Biosci. 5, 389–402 (2008)

    Article  MathSciNet  Google Scholar 

  41. Sato, H., Orenstein, J., Dimitrov, D., Martin, M.: Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles. Virology 186, 712–724 (1992)

    Article  Google Scholar 

  42. Sattentau, Q.: Avoiding the void: cell-to-cell spread of human viruses. Nat. Rev. Microbiol. 6, 28–41 (2008)

    Article  Google Scholar 

  43. Shu, H., Wang, L., Watmough, J.: Global stability of a nonlinear viral infection model with infinitely distribution intracellular delays and CTL immune response. SIAM J. Appl. Math. 73, 1280–1302 (2013)

    Article  MathSciNet  Google Scholar 

  44. Shu, H., Wang, L., Wu, J.: Global dynamics of the Nicholson’s blowflies equation revisited: onset and termination of nonlinear oscillations. J. Differ. Equ. 255, 2565–2586 (2013)

    Article  MathSciNet  Google Scholar 

  45. Sigal, A., Kim, J.T., Balazs, A.B., Dekel, E., Mayo, A., Milo, R., Baltimore, D.: Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477, 95–98 (2011)

    Article  Google Scholar 

  46. Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F., Schwartz, O.: Inefficient HIV replication in mobile lymphocytes. J. Virol. 81, 1000–1012 (2007)

    Article  Google Scholar 

  47. Talbert-Slagle, K., Atkins, K.E., Yan, K.K., Khurana, E., Gerstein, M., Bradley, E.H., Berg, D., Galvani, A.P., Townsend, J.P.: Cellular superspreaders: an epidemiological perspective on HIV infection inside the body. PLoS Pathog. 10, e1004092 (2014)

    Article  Google Scholar 

  48. Thieme, H.R.: Spectral bound and reproduction number for infinite-dimensional population structure and time heterogeneity. SIAM J. Appl. Math. 70, 188–211 (2009)

    Article  MathSciNet  Google Scholar 

  49. Wang, J., Lang, J., Zou, X.: Analysis of an age structured HIV infection model with virus-to-cell infection and cell-to-cell transmission. Nonlinear Anal. RWA 34, 75–96 (2017)

    Article  MathSciNet  Google Scholar 

  50. Wu, J.: Symmetric functional differential equations and neural networks with memory. Trans. Am. Math. Soc. 350, 4799–4838 (1998)

    Article  MathSciNet  Google Scholar 

  51. Yang, Y., Zou, L., Ruan, S.: Global dynamics of a delayed within-host viral infection model with both virus-to-cell and cell-to-cell transmissions. Math. Biosci. 270, 183–191 (2015)

    Article  MathSciNet  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to one anonymous referee for his/her valuable comments and suggestions, which greatly improved the presentation of this work. H. Shu was partially supported by the National Natural Science Foundation of China (No.11601392), Pujiang Talent Program of Shanghai (No. 16PJ1409100) and the Fundamental Research Funds for the Central Universities, Y. Chen and L. Wang were partially supported by NSERC.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hongying Shu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shu, H., Chen, Y. & Wang, L. Impacts of the Cell-Free and Cell-to-Cell Infection Modes on Viral Dynamics. J Dyn Diff Equat 30, 1817–1836 (2018). https://doi.org/10.1007/s10884-017-9622-2

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10884-017-9622-2

Keywords

Navigation