Dynamical behaviors of an HTLV-I infection model with intracellular delay and immune activation delay
- Jinliang Wang^{1},
- Kaifa Wang^{2}Email author and
- Zhichao Jiang^{3}
https://doi.org/10.1186/s13662-015-0577-5
© Wang et al. 2015
Received: 8 February 2015
Accepted: 18 July 2015
Published: 6 August 2015
Abstract
This paper investigates the dynamics of an HTLV-I infection model with intracellular delay and immune activation delay. The primary objective of the study is to consider the effect of the time delay on the stability of the infected equilibrium. Two sharp threshold parameters \(\Re_{0}\) and \(\Re_{1}\) are identified as the basic reproduction number for viral infection and for CTLs response, respectively, which determine the long time behaviors of the viral infection. In particular, our mathematical analysis reveals that a Hopf bifurcation occurs when immune activation delay passes through a critical value. Using the normal form theory and center manifold arguments, the explicit formulae which determine the stability, the direction, and the period of bifurcating periodic solutions are derived. Numerical simulations are given to support the theoretical results.
Keywords
MSC
1 Introduction
Human T-cell leukaemia/lymphoma virus type I (HTLV-I) is a retrovirus infecting primarily CD4^{+} T cells, and the transmission occurs remarkably through direct cell-to-cell contact. It is reported that HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients harbor higher proviral loads in peripheral blood lymphocytes than asymptomatic carriers [1]. Also, a remarkable amount of circulating HTLV-I specific CD8^{+} cytotoxic T lymphocytes (CTLs) circulates in the peripheral blood of HAM/TSP patients present. It is convincing that the persistent cytotoxicity of the CTLs is the reason for the development of a progressive neurologic disease, i.e., HAM/TSP [2, 3], and several HTLV-I-associated diseases.
Understanding the role played by the CTLs in controlling the HTLV-I infection is vital to identifying risk factors for the development of HAM/TSP. Several mathematical models have investigated the dynamics of the interaction in vivo among HTLV-I, the CD4^{+} target cells, and the CTLs immune response in order to explain the pathogenesis of HTLV-I-associated diseases [4–10] and used as a tool to study the role of immune response in the viral dynamics. It is advocated that time delays cannot be ignored in models for immune response [9]. Recently, HTLV-I infection models given by systems of delay differential equations (DDEs) have been studied by several authors, who analyzed the effect of delay in the local and global dynamics of the model, bifurcations, and several rich dynamical behaviors (see, e.g., [1, 10–15] and the references cited therein).
Denote by \(x(t)\), \(y(t)\), \(z(t)\) the concentrations of uninfected, infected, and HTLV-I-specific CD8^{+} CTLs at time t, respectively. In [9], Wang et al. incorporated a time delay into the immune response, \(z'(t) = cy(t-\omega) - bz(t)\), where the CTLs response is activated at a rate proportional to the number of infected cells at a previous time, \(cy(t-\omega)\), and it also decays exponentially at a rate proportional to its current strength bz. Numerical results reveal that stability switches, periodic solutions, and chaotic solutions can be observed. Time delay is commonly incorporated to account for a series of immunological events leading to the CTLs response, and it may arise through a number of different processes. In [15, 16], the authors explored the effect of HTLV-I interaction through a system of delay differential equations (DDEs). The delayed CTLs immune response takes the following form: \(z'(t) = cy(t-\omega)z(t-\omega) - bz(t)\), where the CTLs response activated at time t is proportional to the product of the amount of CTLs at \(t-\omega\) and that of infected cells at \(t-\omega \). It is shown through numerical simulations that delayed CTLs response can lead to sustained oscillations through a Hopf bifurcation.
Recently, HTLV-I model with time delays in the CTL response leading to the coexistence of multiple stable periodic solutions has been studied in [17]. These multiple stable periodic solutions differ in amplitude and period and have their own basins of attraction. In [18], by taking the immune delay as a bifurcation parameter, Xu and Wei theoretically proved the global existence of multiple periodic solutions in HTLV-I infection model with CTL immune response.
In present paper, to further account for the latent period for the cell to cell infection, we assume that virus transmission occurs after the virus entry with a constant time lag \(\tau> 0\). Here, the intracellular delay τ describes the latent period between the time when target cells are infected and the time when infected cells start producing virions to integration, i.e., CD4^{+} T cells infected at time t will be activated at time \(t +\tau\). The number of actively infected target cells at time t is given by a delayed mass-action (bilinear incidence) term \(\beta e^{-d\tau}x(t-\tau)y(t-\tau)\), where \(e^{-d\tau}\) describes the probability of infected target cells surviving the period of intracellular delay from \(t-\tau\) to t. Constant d denotes the death rate for infected cells (but not yet virus producing cells).
The aim of the present paper is to carry out a complete mathematical analysis of dynamic behaviors of system (1.2) and find out the different influences between intracellular delay and immune activation delay. The paper is organized as follows. In Section 2, we present preliminary results of system (1.2), including positivity and boundedness of solutions, the existence of equilibria, and the definition of the basic reproduction numbers for viral infection (\(\Re_{0}\)) and for CTLs response (\(\Re _{1}\)). Section 3 is devoted to the global dynamics of system (1.2) when \(\Re_{1}\leq1\). Using the two key threshold parameters \(\Re_{0}\) and \(\Re_{1}\), we establish the global dynamics of system (1.2) by the techniques of Lyapunov functionals. When \(\Re_{1}>1\), Section 4 first gives the global dynamics of system (1.2) in the case where τ is present and ω is absent. The results indicate that the intracellular delay does not affect the stability of the system. Thus, we can neglect the intracellular delay τ in system (1.2). Therefore, we identify parameter regimes in which immune activation delay ω can destabilize the HAM/TSP equilibrium and lead to a Hopf bifurcation. Using the normal form theory and center manifold argument, the explicit formulae which determine the stability and direction of bifurcated periodic solutions are derived. Numerical simulations are carried out to explain the mathematical conclusions in Section 5. The last section ends with a summary and discussion.
2 Preliminaries
Proposition 2.1
Under initial conditions in (1.3), all solutions of system (1.2) are positive and ultimately bounded in \(\mathcal{C}\).
Proof
By the existence and uniqueness theorem (Theorem 2.1 of Kuang [20]) of DDEs, there exists \(t_{0} > 0\) such that there exists a solution \((x(t), y(t), z(t))\) of system (1.2) for \(0 < t < t_{0}\). We assume that there exists a solution of system (1.2) for \(0 < t < t_{1}\) for positive \(t_{1}\), where the existence is assured by the theorem stated above.
First, we prove that \(x(t)\) is positive for all \(t \geq0\). Assuming the contrary and letting \(t_{1} > 0\) be the first time such that \(x(t_{1}) = 0\), we have \(x'(t_{1}) = \lambda> 0\) by the first equation of system (1.2). Hence \(x(t) < 0\) for \(t\in(t_{1}-\varepsilon, t_{1})\), where \(\varepsilon> 0\) is a sufficiently small constant. This contradicts \(x(t) > 0\) for \(t\in[0, t_{1})\). It follows that \(x(t) > 0\) for \(t > 0\) as long as \(x(t)\) exists.
We summarize the above analysis in the following result.
Proposition 2.2
If \(\Re_{0} \leq1\), \(E_{0} =(\lambda/d_{1}, 0, 0)\) is the only equilibrium in Γ. If \(\Re_{1} \leq1 < \Re_{0}\), the carrier equilibrium \(E_{1} = (x_{1}, y_{1}, 0)\) appears and is the only chronic-infection equilibrium in Γ. If \(\Re_{1} > 1\), both the carrier equilibrium \(E_{1}\) and the HAM/TSP equilibrium \(E_{2}= (x_{2}, y_{2}, z_{2})\) appear.
3 Dynamics of system (1.2) for \(\Re_{1}\leq1\)
In what follows, we investigate the dynamics of system (1.2) when \(\Re_{1}\leq1\). We begin by using the inequality \(g(x) = x- 1-\ln x\geq g(1)=0\) with equality holding if and only if \(x=1\), which can simplify many of the expressions in the following calculations. Note that \(g : \mathbb {R}^{+}\rightarrow \mathbb{R}^{+}\) has strict global minimum \(g(1) = 0\).
We have the following theorem.
Theorem 3.1
- (i)
If \(\Re_{0}\leq1\), then \(E_{0}\) is globally asymptotically stable.
- (ii)
If \(\Re_{1} \leq1 < \Re_{0}\), then \(E_{1}\) is globally asymptotically stable.
Proof
Remark 3.1
Theorem 3.1 gives a complete picture of global dynamics of system (1.2) for the case where \(\Re_{1} \leq1\). It is shown that \(\Re _{0}\) and \(\Re_{1}\) as two sharp threshold parameters together determine the outcomes of the HTLV-I infection: when \(\Re_{0} \leq1\), then the HTLV-I viruses are cleared; when \(\Re_{1} \leq1 < \Re_{0}\), then HTLV-I infection becomes chronic with no persistent CTLs immune response. The patient remains as an asymptotic carrier.
4 Dynamics of system (1.2) when \(\Re_{1}>1\)
From Proposition 2.2, when \(\Re_{1} > 1\), the HAM/TSP equilibrium \(E_{2}= (x_{2}, y_{2}, z_{2})\) appears and both HTLV-I infection and CTLs immune response will persist. The patient has a high risk to developing HAM/TSP. In this section, we will focus on the stability of the HAM/TSP equilibrium \(E_{2}\).
Hence we arrive at the following theorem on the global dynamics of (4.1) with (4.2).
Theorem 4.1
- (i)
If \(\Re_{0}\leq1\), then the infection-free equilibrium \(E_{0}(x_{0}, 0, 0)\) is globally asymptotically stable;
- (ii)
If \(\Re_{1}\leq1<\Re_{0}\), then the immune-free equilibrium \(E_{1}(x_{1}, y_{1}, 0)\) is globally asymptotically stable;
- (iii)
If \(\Re_{1} > 1\), then the HAM/TSP equilibrium \(E_{2}(x_{2}, y_{2}, z_{2})\) is globally asymptotically stable.
Remark 4.1
As to the main results in Song et al. [21], Theorem 4.1 gives a confirmative answer that there are no sustained oscillations to occur when the immune response is not incorporated with time delay.
Next, we will use the delay \(\omega> 0\) as a bifurcation parameter and investigate stability changes at the HAM/TSP equilibrium \(E^{*}\). We will show that a Hopf bifurcation occurs for an open set of parameter values. This rigorously establishes that periodic oscillations exist in system (4.3).
- (1)
If \(\Delta\leq 0\), then \(G'(u) \geq0\), and thus \(G(u)\) is monotonically increasing. Therefore, by \(-c_{0}^{2}=G(0)<0\) and \(\lim_{u\rightarrow\infty} G(u) = \infty\), we know that (4.9) has at least one positive root, and characteristic roots can cross the imaginary axis.
- (2)If \(\Delta> 0\), then the graph of \(G(u)\) has critical pointsClearly, \(G''(u^{*})=2\sqrt{\Delta}>0\) and \(G''(u^{**})=-2\sqrt{\Delta }<0\), it follows that \(u^{*}\) and \(u^{**}\) are the local minimum and the local maximum of \(G(u)\), respectively.$$u^{*}=\frac{-(a_{1}^{2}-2b_{1})+\sqrt{\Delta}}{3}, \qquad u^{**}=\frac {-(a_{1}^{2}-2b_{1})-\sqrt{\Delta}}{3}. $$
Theorem 4.2
If \(\Delta>0\), \(u^{*}=\frac{-(a_{1}^{2}-2b_{1})+\sqrt{\Delta}}{3}>0\) and \(G(u^{*})<0\), then there exist \(\omega_{0} > 0\) and \(p_{0}\) as in (4.13) such that the HAM/TSP equilibrium \(E^{*}\) is asymptotically stable for \(\omega\in[0, \omega_{0})\). Furthermore, if \(G'(p_{0}^{2})\neq0\), then system (4.3) undergoes a Hopf bifurcation at the HAM/TSP equilibrium \(E^{*}\) when \(\omega=\omega_{0}\).
Proof
We have identified parameter regimes in which delay ω can destabilize the HAM/TSP equilibrium and lead to a Hopf bifurcation. This shows that when \(\omega> \omega_{0}\) and is close to \(\omega_{0}\), periodic solutions exist. As a consequence, when HAM/TSP develops, the CD4^{+} count, proviral load, and the HTLV-I specific CTLs frequency can oscillate around the equilibrium level. Next, using techniques from normal form and center manifold theory (see, e.g., Hassard et al. [22]), we study the direction of the Hopf bifurcation and the stability of the bifurcating periodic solutions when \(\omega=\omega_{0}\).
Theorem 4.3
\(\mu_{2}\) determines the direction of the Hopf bifurcation: if \(\mu_{2} > 0\) (\(\mu_{2} < 0\)), then the Hopf bifurcation is supercritical (subcritical) and the bifurcating periodic solutions exist for \(\omega > \omega_{0}\) (\(\omega< \omega_{0}\)); \(\beta_{2}> 0\) (\(\beta_{2} < 0\)) determines the stability of bifurcating periodic solutions: the bifurcating periodic solutions are orbitally asymptotically stable (unstable) if \(\omega> \omega_{0}\) (\(\omega< \omega_{0}\)).
5 Numerical simulation
In this section, we further investigate the dynamical behaviors of (4.3) through numerical simulations with the aid of Mathematica. It is shown that the parameter values can be chosen simply to establish the possibility for oscillations in the viral load and T cell populations.
As in [23, 24], time is measured in days and x, y, z have units mm^{−3}. In the absence of infection, the rate of production of healthy CD4^{+} T cells from the bone marrow falls in the range of 100-1,500 cells/mm^{3}/day [23, 24], and all three populations considered in our model display natural death rates between 0.001-5/day.
6 Conclusion and discussion
In this paper, we have investigated the dynamics of an HTLV-I model which incorporates intracellular delay and immune activation delay based on the rigorous mathematical analysis. Using two threshold parameters \(\Re_{0}\) and \(\Re_{1}\), named as the basic reproduction number for viral persistence and for CTLs response, the global dynamics of the proposed system can be obtained by constructing suitable Lyapunov functionals under LaSalle’s invariance principle. Our results show that the intracellular delay τ does not affect the stability of the HAM/TSP equilibrium, but the immune activation delay can destabilize the equilibrium and lead to a Hopf bifurcation.
As to the previous studies, Wodarz et al. [5], Li and Shu [15, 25], Song et al. [21], Wang et al. [9], Canabarro et al. [16], our results are the first to establish the existence of a Hopf bifurcation in a HTLV-I model with delayed immune response (\(z'(t)=cy(t-\omega )z(t)-bz\)) using rigorous mathematical analysis. On the other hand, the results in the present paper (combined with the results in [25] and [15]) show that a mitosis component is not required for sustained oscillations to occur when the immune response is incorporated into the model. These results together have largely enriched our understanding of the effects of intracellular delays in dynamics of viral infection and its interaction with the CTLs immune response. Further, numerical simulation in Figure 1 reveals that the stability switch occurs at critical value of \(\omega_{0}\), and the periodic solutions exist with an increasing amplitude when ω continues to increase.
HTLV-I infection is rarely cleared from the body. The dynamical outcomes that are biologically relevant are the carrier state and HAM/TSP state. Furthermore, considering that the large number of HTLV-I infected patients are asymptomatic carriers, it is a realistic control and treatment strategy in preventing carriers from developing HAM/TSP by keeping the threshold parameter \(\Re_{1}\) below 1, which may have potential implications for future studies.
Declarations
Acknowledgements
The authors would like to thank the anonymous referees and the editor for very helpful suggestions and comments which led to improvements of our original paper. JW was supported by National Natural Science Foundation of China (Nos. 11401182 and 11471089), Natural Science Foundation of Heilongjiang Province (No. A201415), Science and Technology Innovation Team in Higher Education Institutions of Heilongjiang Province (No. 2014TD005), Overseas Studies of Heilongjiang Education Departments (2014), Youth Foundation of Heilongjiang University, project funded by China Post-doctoral Science Foundation (No. 2014M552295) and project funded by Chongqing Postdoctoral Foundation (No. Xm2014024). KW was supported by the National Natural Science Foundation of China (No. 11271369).
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Authors’ Affiliations
References
- Gomez-Acevedo, H, Li, MY, Jacobson, S: Multi-stability in a model for CTL response to HTLV-I infection and its consequences in HAM/TSP development and prevention. Bull. Math. Biol. 72, 681-696 (2010) MathSciNetView ArticleMATHGoogle Scholar
- Gessain, A, Barin, F, Vernant, JC, Gout, O, Maurs, L, Calender, A, de Thé, G: Antibodies to human T-lymphotropic virus type-I in patient with tropical spastic paraparesis. Lancet 2, 407-410 (1985) View ArticleGoogle Scholar
- Osame, M, Usuku, K, Izumo, S, Ijichi, N, Aminati, H, Igata, A, Matsumoto, M, Tara, M: HTLV-I-associated myelopathy: a new clinical entity. Lancet 1, 1031-1032 (1986) View ArticleGoogle Scholar
- Nowak, MA, May, RM: Virus Dynamics: Mathematical Principles of Immunology and Virology. Cambridge University Press, Cambridge (2000) Google Scholar
- Wodarz, D, Bangham, CRM: Evolutionary dynamics of HTLV-I. J. Mol. Evol. 50, 448-455 (2000) Google Scholar
- Wodarz, D, Nowak, MA, Bangham, CRM: The dynamics of HTLV-I and the CTL response. Immunol. Today 20, 220-227 (1999) View ArticleGoogle Scholar
- Burić, N, Mudrinic, M, Vasović, N: Time delay in a basic model of the immune response. Chaos Solitons Fractals 12, 483-489 (2001) View ArticleMATHGoogle Scholar
- Lang, J, Li, MY: Stable and transient periodic oscillations in a mathematical model for CTL response to HTLV-I infection. J. Math. Biol. 65, 181-199 (2012) MathSciNetView ArticleMATHGoogle Scholar
- Wang, K, Wang, W, Pang, H, Liu, X: Complex dynamic behavior in a viral model with delayed immune response. Physica D 226, 197-208 (2007) MathSciNetView ArticleMATHGoogle Scholar
- Wang, L, Li, MY, Kirschner, D: Mathematical analysis of the global dynamics of a model for HTLV-I infection and ATL progression. Math. Biosci. 179, 207-217 (2002) MathSciNetView ArticleMATHGoogle Scholar
- Bangham, CRM: The immune response to HTLV-I. Curr. Opin. Immunol. 12, 397-402 (2000) View ArticleGoogle Scholar
- Bangham, CRM: The immune control and cell-to-cell spread of human T-lymphotropic virus type 1. J. Gen. Virol. 84, 3177-3189 (2003) View ArticleGoogle Scholar
- Eshima, N, Tabata, M, Okada, T, Karukaya, S: Population dynamics of HTLV-I infection: a discrete-time mathematical epidemic model approach. Math. Med. Biol. 20, 29-45 (2003) View ArticleMATHGoogle Scholar
- Jacobson, S: Immunopathogenesis of human T cell lymphotropic virus type I-associated neurologic disease. J. Infect. Dis. 186, S187-S192 (2002) View ArticleGoogle Scholar
- Li, MY, Shu, H: Global dynamics of a mathematical model for HTLV-I infection of CD4^{+} T cells with delayed CTL response. Nonlinear Anal., Real World Appl. 13, 1080-1092 (2012) MathSciNetView ArticleMATHGoogle Scholar
- Canabarro, AA, Gléria, IM, Lyra, ML: Periodic solutions and chaos in a non-linear model for the delayed cellular immune response. Physica A 342, 234-241 (2004) View ArticleGoogle Scholar
- Li, MY, Shu, H: Multiple stable periodic oscillations in a mathematical model of CTL response to HTLV-I infection. Bull. Math. Biol. 73, 1774-1793 (2011) MathSciNetView ArticleMATHGoogle Scholar
- Sun, X, Wei, J: Global existence of periodic solutions in an infection model. Appl. Math. Lett. 48, 118-123 (2015) MathSciNetView ArticleGoogle Scholar
- Huang, G, Yokoi, H, Takeuchi, Y, Kajiwara, T, Sasaki, T: Impact of intracellular delay, immune activation delay and nonlinear incidence on viral dynamics. Jpn. J. Ind. Appl. Math. 28, 383-411 (2011) MathSciNetView ArticleMATHGoogle Scholar
- Kuang, K: Delay Differential Equations with Applications in Population Dynamics. Academics Press, San Diego (1993) MATHGoogle Scholar
- Song, X, Wang, S, Dong, J: Stability properties and Hopf bifurcation of a delayed viral infection model with lytic immune response. J. Math. Anal. Appl. 373, 345-355 (2011) MathSciNetView ArticleMATHGoogle Scholar
- Hassard, BD, Kazarinoff, ND, Wan, YH: Theory and Application of Hopf Bifurcation. Cambridge University Press, Cambridge (1981) Google Scholar
- de Leenheer, P, Smith, HL: Virus dynamics: a global analysis. SIAM J. Appl. Math. 63, 1313-1327 (2002) Google Scholar
- Perelson, AS, Kirschner, DE, de Boer, R: Dynamics of HIV infection of CD4^{+} T cell. Math. Biosci. 144, 81-125 (1993) View ArticleGoogle Scholar
- Li, MY, Shu, H: Impact of intracellular delays and target-cell dynamics on in vivo viral infections. SIAM J. Appl. Math. 70, 2434-2448 (2010) MathSciNetView ArticleMATHGoogle Scholar