Analysis of the dynamics of a delayed HIV pathogenesis model

In this paper, considering full Logistic proliferation of CD4⁺ T cells, we study an HIV pathogenesis model with antiretroviral therapy and HIV replication time. We first analyze the existence and stability of the equilibrium, and then investigate the effect of the time delay on the stability of the infected steady state. Sufficient conditions are given to ensure that the infected steady state is asymptotically stable for all delay. Furthermore, we apply the Nyquist criterion to estimate the length of delay for which stability continues to hold, and investigate the existence of Hopf bifurcation by using a delay τ as a bifurcation parameter. Finally, numerical simulations are presented to illustrate the main results.     

A fractional-order model of HIV infection with drug therapy effect

In this paper, the fractional-order model that describes HIV infection of CD4⁺ T cells with therapy effect is given. Generalized Euler Method (GEM) is employed to get numerical solution of such problem. The fractional derivatives are described in the Caputo sense.     

On global stability of an HIV pathogenesis model with cure rate

In this paper, applying both Lyapunov function techniques and monotone iterative techniques, we establish new sufficient conditions under which the infected equilibrium of an HIV pathogenesis model with cure rate is globally asymptotically stable. By giving an explicit expression for eventual lower bound of the concentration of susceptible CD4⁺ T cells, we establish an affirmative partial answer to the numerical simulations investigated in the recent paper [Liu, Wang, Hu and Ma, Global stability of an HIV pathogenesis model with cure rate, Nonlinear Analysis RWA (2011) 12 : 2947–2961]. Our monotone iterative techniques are applicable for the small and large growth rate in logistic functions for the proliferation rate of healthy and infected CD4⁺ T cells. Copyright © 2014 John Wiley & Sons, Ltd.     

Stability of HIV/HTLV-I co-infection model with delays

In this paper, we formulate a within-host dynamics model for HIV/HTLV-I co-infection under the influence of cytotoxic T lymphocytes (CTLs). The model incorporates silent HIV-infected CD4⁺T cells and silent HTLV-infected CD4⁺T cells. The model includes two routes of HIV transmission, virus to cell (VTC) and cell to cell (CTC). It also incorporates two modes of HTLV-I transmission, horizontal transmission via direct CTC contact and vertical transmission through mitotic division of Tax-expressing HTLV-infected cells. The model takes into account five types of distributed-time delays. We analyze the model by proving the nonnegativity and boundedness of the solutions, calculating all possible equilibria, deriving a set of key threshold parameters, and proving the global stability of all equilibria. The global asymptotic stability of all equilibria is established by utilizing Lyapunov function and LaSalle's invariance principle. We present numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we discuss the effect of HTLV-I infection on the HIV dynamics and vice versa.     

Long term dynamics in a mathematical model of HIV-1 infection with delay in different variants of the basic drug therapy model

Infection with HIV-1, degrading the human immune system and recent advances of drug therapy to arrest HIV-1 infection, has generated considerable research interest in the area. Bonhoeffer et al. (1997) [1], introduced a population model representing long term dynamics of HIV infection in response to available drug therapies. We consider a similar type of approximate model incorporating time delay in the process of infection on the healthy T cells which, in turn, implies inclusion of a similar delay in the process of viral replication. The model is studied both analytically and numerically. We also include a similar delay in the killing rate of infected CD4⁺ T cells by Cytotoxic T-Lymphocyte (CTL) and in the stimulation of CTL and analyse two resulting models numerically.The models with no time delay present have two equilibria: one where there is no infection and a non-trivial equilibrium where the infection can persist. If there is no time delay then the non-trivial equilibrium is locally asymptotically stable. Both our analytical results (for the first model) and our numerical results (for all three models) indicate that introduction of a time delay can destabilize the non-trivial equilibrium. The numerical results indicate that such destabilization occurs at realistic time delays and that there is a threshold time delay beneath which the equilibrium with infection present is locally asymptotically stable and above which this equilibrium is unstable and exhibits oscillatory solutions of increasing amplitude.     

Bifurcation analysis of the HIV‐1 within host model

In this paper, a bifurcation solution's analysis is proposed for an HIV‐1 within the host model around its chronic equilibrium point, this is carried out based on Lyapunov–Schmidt approach. It is shown that the coefficient b, which represents the healthy CD4⁺ T‐cells growth rate, is a bifurcation parameter; this means that the rate of multiplication of healthy cells can have serious effects on the qualitative dynamical properties and structural stability of the infection evolution dynamics. Copyright © 2015 John Wiley & Sons, Ltd.     

The role of CD4 T cells in immune system activation and viral reproduction in a simple model for HIV infection

CD4 T cells play a fundamental role in the adaptive immune response including the stimulation of cytotoxic lymphocytes (CTLs). Human immunodeficiency virus (HIV) which infects and kills CD4 T cells causes progressive failure of the immune system. However, HIV particles are also reproduced by the infected CD4 T cells. Therefore, during HIV infection, infected and healthy CD4 T cells act in opposition to each other, reproducing virus particles and activating and stimulating cellular immune responses, respectively. In this investigation, we develop and analyze a simple system of four ordinary differential equations that accounts for these two opposing roles of CD4 T cells. The model illustrates the importance of the CTL immune response during the asymptomatic stage of HIV infection. In addition, the solution behavior exhibits the two stages of infection, asymptomatic and final AIDS stages. In the model, a weak immune response results in a short asymptomatic stage and faster development of AIDS, whereas a strong immune response illustrates the long asymptomatic stage. A model with a latent stage for infected CD4 T cells is also investigated and compared numerically with the original model. The model shows that strong stimulation of CTLs by CD4 T cells is necessary to prevent progression to the AIDS stage.     

Stabilization of HIV/AIDS model by receding horizon control

This work concerns the stabilization of uninfected steady state of an ordinary differential equation system modeling the interaction of the HIV virus and the immune system of the human body. The control variable is the drug dose, which, in turn, affects the rate of infection of CD4⁺ T cells by HIV virus. The feedback controller is constructed by a variant of the receding horizon control (RHC) method. Simulation results are discussed.     

Global properties of a class of HIV infection models with Beddington–DeAngelis functional response

In this paper, the global properties of a class of human immunodeficiency virus (HIV) models with Beddington–DeAngelis functional response are investigated. Lyapunov functions are constructed to establish the global asymptotic stability of the uninfected and infected steady states of three HIV infection models. The first model considers the interaction process of the HIV and the CD4 ⁺ T cells and takes into account the latently and actively infected cells. The second model describes two co‐circulation populations of target cells, representing CD4 ⁺ T cells and macrophages. The third model is a two‐target‐cell model taking into account the latently and actively infected cells. We have proven that if the basic reproduction number R₀ is less than unity, then the uninfected steady state is globally asymptotically stable, and if R₀ > 1, then the infected steady state is globally asymptotically stable. Copyright © 2012 John Wiley & Sons, Ltd.     

HIV dynamics: Analysis and robust multirate MPC-based treatment schedules

Analysis and control of human immunodeficiency virus (HIV) infection have attracted the interests of mathematicians and control engineers during the recent years. Several mathematical models exist and adequately explain the interaction of the HIV infection and the immune system up to the stage of clinical latency, as well as viral suppression and immune system recovery after treatment therapy. However, none of these models can completely exhibit all that is observed clinically and account the full course of infection. Besides model inaccuracies that HIV models suffer from, some disturbances/uncertainties from different sources may arise in the modelling. In this paper we study the basic properties of a 6-dimensional HIV model that describes the interaction of HIV with two target cells, CD4⁺ T cells and macrophages. The disturbances are modelled in the HIV model as additive bounded disturbances. Highly Active AntiRetroviral Therapy (HAART) is used. The control input is defined to be dependent on the drug dose and drug efficiency. We developed treatment schedules for HIV infected patients by using robust multirate Model Predictive Control (MPC)-based method. The MPC is constructed on the basis of the approximate discrete-time model of the nominal model. We established a set of conditions, which guarantee that the multirate MPC practically stabilizes the exact discrete-time model with disturbances. The proposed method is applied to the stabilization of the uninfected steady state of the HIV model. The results of simulations show that, after initiation of HAART with a strong dosage, the viral load drops quickly and it can be kept under a suitable level with mild dosage of HAART. Moreover, the immune system is recovered with some fluctuations due to the presence of disturbances.     

A differential equation model of HIV infection of CD4T-cells with cure rate

A differential equation model of HIV infection of CD4⁺T-cells with cure rate is studied. We prove that if the basic reproduction number R₀<1, the HIV infection is cleared from the T-cell population and the disease dies out; if R₀>1, the HIV infection persists in the host. We find that the chronic disease steady state is globally asymptotically stable if R₀>1. Furthermore, we also obtain the conditions for which the system exists an orbitally asymptotically stable periodic solution. Numerical simulations are presented to illustrate the results.     

A Delayed HIV Infection Model with the Homeostatic Proliferation of CD4+ T Cells

Acta Mathematicae Applicatae Sinica, English Series - In this paper, we investigate a delayed HIV infection model that considers the homeostatic proliferation of CD4+ T cells. The existence and...     

Bifurcation analysis of a multidelayed HIV model in presence of immune response and understanding of in‐host viral dynamics

In this paper, we proposed a multidelayed in‐host HIV model to represent the interaction between human immunodeficiency virus and immune response. One delay was considered to incorporate the time required by the virus for various intracellular events to make a host cell productively infective, and the second delay was introduced to take into account the time required for adaptive immune system to respond against infection. We extensively analyzed this multidelayed model analytically and numerically. We show that delay may have both destabilizing and stabilizing effects even when the system contains a single immune response delay. It happens when there exists two sequences of critical values of this delay. If the system starts with stable state in absence of delay, then the smallest value of these critical delays causes instability and the next higher value causes stability. The system may also show stability switching for different values of the virus replication factor. These results demonstrate the possible reasons of intrapatients and interpatients variability of CD4⁺ T cells and virus counts in HIV‐infected patients.     

Optimal homotopy analysis of a chaotic HIV-1 model incorporating AIDS-related cancer cells

The studies of nonlinear models in epidemiology have generated a deep interest in gaining insight into the mechanisms that underlie AIDS-related cancers, providing us with a better understanding of cancer immunity and viral oncogenesis. In this article, we analyze an HIV-1 model incorporating the relations between three dynamical variables: cancer cells, healthy CD4 ⁺ T lymphocytes, and infected CD4 ⁺ T lymphocytes. Recent theoretical investigations indicate that these cells interactions lead to different dynamical outcomes, for instance to periodic or chaotic behavior. Firstly, we analytically prove the boundedness of the trajectories in the system’s attractor. The complexity of the coupling between the dynamical variables is quantified using observability indices. Our calculations reveal that the highest observable variable is the population of cancer cells, thus indicating that these cells could be monitored in future experiments in order to obtain time series for attractor’s reconstruction. We identify different dynamical behaviors of the system varying two biologically meaningful parameters: r ₁, representing the uncontrolled proliferation rate of cancer cells, and k ₁, denoting the immune system’s killing rate of cancer cells. The maximum Lyapunov exponent is computed to identify the chaotic regimes. Considering very recent developments in the literature related to the homotopy analysis method (HAM), we calculate the explicit series solutions of the cancer model and focus our analysis on the dynamical variable with the highest observability index. An optimal homotopy analysis approach is used to improve the computational efficiency of HAM by means of appropriate values for the convergence control parameter, which greatly accelerate the convergence of the series solution. The approximated analytical solutions are used to compute density plots, which allow us to discuss additional dynamical features of the model.     

A delay differential equation model of HIV infection of CD4+ T-cells with cure rate

A delay differential equation as a mathematical model that described HIV infection of CD4⁺ T-cells is analyzed. When the constant death rate of infected but not yet virus-producing cells is equal to zero, the stability of the non-negative equilibria and the existence of Hopf bifurcation are investigated. A stability switch in the system due to variation of delay parameter has been observed, so is the phenomena of Hopf bifurcation and stable limit cycle. The estimation of the length of delay to preserve stability has been calculated. Further, when the constant death rate of infected but not yet virus-producing cells is not equal to zero, by using the geometric stability switch criterion in the delay differential system with delay dependent parameters, we present that stable equilibria become unstable as the time delay increases. Numerical simulations are carried out to explain the mathematical conclusions.     

The impact of zidovudine (AZT) therapy on the survivability of those with the progressive HIV infection

An analysis of the data regarding the impact of zidovudine therapy on the Survivability of those with progressive HIV disease demonstrates that this therapy extends longevity for perhaps 5.5 months on the average but does not prevent the disease from eventually being fatal. All of the benefits of zidovudine therapy in extending survivability appear to accrue within a relatively short treatment period, perhaps within a few months, but the effectiveness of this drug wanes in time, suggesting that zidovudine therapy could eventually be stopped without influencing survivability. Since the efficacy of zidovudine therapy in extending survivability appears to be independent of the stage of the HIV infection in infecteds whose CD4 T-cell densities fall below 200 cells/mm³, zidovudine therapy should be initiated when the patient's infection reaches a potentially fatal stage. Zidovudine therapy may be viewed as causing the HIV infection to regress to a previous stage of the disease, but the infection's progression promptly resumes and follows a course similar to one uninfluenced by zidovudine.     

Global dynamics of a mathematical model for HTLV-I infection of CD4 T cells with delayed CTL response

Human T-cell leukaemia virus type I (HTLV-I) preferentially infects the CD4⁺ T cells. The HTLV-I infection causes a strong HTLV-I specific immune response from CD8⁺ cytotoxic T cells (CTLs). The persistent cytotoxicity of the CTL is believed to contribute to the development of a progressive neurologic disease, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We investigate the global dynamics of a mathematical model for the CTL response to HTLV-I infection in vivo. To account for a series of immunological events leading to the CTL response, we incorporate a time delay in the response term. Our mathematical analysis establishes that the global dynamics are determined by two threshold parameters R₀ and R₁, basic reproduction numbers for viral infection and for CTL response, respectively. If R₀≤1, the infection-free equilibrium P₀ is globally asymptotically stable, and the HTLV-I viruses are cleared. If R₁≤1<R₀, the asymptomatic-carrier equilibrium P₁ is globally asymptotically stable, and the HTLV-I infection becomes chronic but with no persistent CTL response. If R₁>1, a unique HAM/TSP equilibrium P₂ exists, at which the HTLV-I infection is chronic with a persistent CTL response. We show that the time delay can destabilize the HAM/TSP equilibrium, leading to Hopf bifurcations and stable periodic oscillations. Implications of our results to the pathogenesis of HTLV-I infection and HAM/TSP development are discussed.