Global Stability of HIV-1 Infection Model with Two Time Delays

and Applied Analysis 3 Calculating the derivative ofN(t) along the solution of system (2) and by positivity of the solutions, we have ?̇? (t) = e −mτ 1 s − e −mτ 1 dx (t − τ 1 ) − 1 2 ay (t) − au 2k V (t) − pb


Introduction
As well known, in recent years the population dynamics of infectious diseases have been extensively studied [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].Particularly, the HIV (human immunodeficiency virus) has been extensively studied in [1-5, 7-11, 14, 15, 20] and became a global problem.The HIV infection is characterized by three different phases, namely, the primary infection, clinically asymptomatic stage (chronic infection), and acquired immunodeficiency syndrome (AIDS) or drug therapy.During primary infection, viral load in the peripheral blood experiences a substantial increase to the peak level, followed by decline to the steady state, which is referred to as the viral set point.Extremely high viral load during primary infection leads to the activation of CD4 + T cells, which are recognized as cytotoxic T cells (CTL) capable of suppressing viral replication.Viral decline from the peak is due to the control by these immune cells and/or limited target cell availability.The viral set point has been shown to be predictive for the pace of disease development [8].Clinical research combined with mathematical modeling has enhanced progress in the understanding of HIV-1 infection [4].This is because mathematical models can offer a way to study the dynamics of viral load in vivo and can be very useful in understanding the interaction between virus and host cell.
On the other hand, in the real situation, there may be a lag between the time target cells are contacted by the virus particles and the time the contacted cells become actively affected meaning that the contacting virions enter cells.This can be explained by the initial (or eclipse) phase of the virus life cycle, which include all stages from viral attachment until the time that the host cell contains the infectious viral particles in its cytoplasm [3].Research [8] has shown that models of HIV-1 infection that include intracellular delays are more accurate representations of the biology and change the estimated values of kinetic parameters when compared to models without delays.Therefore, we should introduce time delays into model foundation, which will have more resemblance to the real ecosystem.In the last decade, the HIV-infection models with time delay have been studied by many authors, and time delays of one type or another have been incorporated into biological models by many authors (e.g., [1-5, 8-11, 14, 15, 20] and the references cited therein).Here we include an intracellular delay as well as immune delay.There are some models which include an intracellular delay [1][2][3][4][5]; some authors believe that time delays can not be ignored in models for immune response [6,7].
The salient features of the mechanism of the immune response during viral infection are as follows.First, the free virus enters its target, a susceptible cell.Inside this cell it replicates itself.And this susceptible cell becomes an infected cell.Then the infected cell dies and releases new viruses; these viruses begin to infect other susceptible cells.During the process of viral infection, the host is induced which is initially rapid and nonspecific (natural killer cells, macrophage cell, etc.) and then delayed and specific (cytotoxic T lymphocyte cells, antibody cell).But in most virus infections cytotoxic T lymphocyte (CTL) cells which attack infected cells, and antibody cell which attack viruses, play a critical part in antiviral defense.In order to investigate the role of the population dynamics of viral infection with CTL response, Pawelek et al. [8] constructed a mathematical model describing the basic dynamics of the interaction between the uninfected target cells, productively infected cells, free virus, and the CTL response cells, which is described by the following differential equation: where the uninfected target cells are denoted by (), productively infected cells are denoted by (), free virus is denoted by V(), and the CTL response cells are denoted by ().The parameter  represents the rate at which new target cells are created,  is the death rate of uninfected target cells,  is the infection rate of uninfected cells by virus,  is the death rate of productively infected cells,  represents the killing rate of infected cells by CTL response cells,  is the rate of the virus particles produced by infected cells,  is the viral clearance rate constant,  is the rate at which the CTL response is produced, and  is the death rate of the CTL response.
In order to incorporate the intracellular phase of the virus life cycle, we assume that virus production occurs after the virus entry by the constant delay  1 .The recruitment of virus-producing cells at time  is given by the number of the uninfected CD4 + T cells that were newly infected at time  −  1 and are still alive at time  [9,10].If we assume constant death rates  for infected CD4 + T cells but not yet producing virus particles, the probability of surviving the time period from  −  1 to  is exp − 1 .And the immune response plays an important role in eliminating or controlling the disease after human body is infected by virus.Antigenic stimulation generating CTLs may need a period of time  2 ; that is, the CTL response at time  may depend on the population of antigen at a period time  −  2 [11].
Therefore, based on the discussion above, the model can be written in the following form: ( The organization of this paper is as follows.In the next section we deal with some basic properties such as positivity and boundedness of the solutions and existence of equilibria of system (2).In Section 3, we prove the local stability of three possible equilibria.Further, by using the well-known Lyapunov-Lasalle invariance principle, we prove the global asymptotic stability of the infection-free equilibrium, CTLabsent infection equilibrium, and a special case of CTLpresent equilibrium.By bifurcation theory, we also can prove that there is a stability switch for another special case for CTL-present equilibrium.In Section 4, one example is given to illustrate that our main results are applicable.In the final section, we offer a brief conclusion.
First we will discuss the positivity and boundedness of the solution.
Proof.From (2), we have This means that all the solutions of system (2) with initial condition (3) are positive.To prove the boundedness of the solution, denote Calculating the derivative of () along the solution of system (2) and by positivity of the solutions, we have where  = min{, /2, , }.This implies that () is bounded for large .So (), (), V(), and () are ultimately bounded.Next we will discuss the equilibria of system (2).The following is the basic reproductive ratio of system (2) which describes the average number of newly infected cells generated from one infected cell at the beginning of the infectious process: By direct calculation we have that system (2) has three equilibria.Infection-free equilibrium  0 = ( 0 , 0, 0, 0) = (/, 0, 0, 0).If  0 > 1, there is a CTL-absent infection equilibrium If  0 > 1 + /, then there is a CTL-present infection equilibrium

Stability Analysis of Delay Model (2)
In this section, we will analyse locally and globally asymptotic stability of the three equilibria.

Stability of Infection-Free Equilibrium 𝐸 0
Theorem 2. For the infection-free equilibrium  0 of system (2); (i) if  0 < 1, then  0 is locally asymptotically stable; Proof.First, we will prove the local stability of  0 .At the infection-free equilibrium  0 , the characteristic equation for the corresponding linearized system of (2) becomes Two of the roots of the characteristic equation ( 10) are  1 = −, and  2 = −.The remaining two roots are obtained by considering the following equation: If  has a nonnegative real part, then the modulus of the lefthand side of (11) satisfies while the modulus of the right-hand side (11) satisfies This leads to a contradiction.Thus, when  0 < 1, all the eigenvalues have negative real parts, and hence the infectionfree steady state is locally asymptotically stable.

Stability of CTL-Present
Infection Equilibrium  2 .On the stability analysis of CTL-present infection equilibrium  2 , we only consider the two special cases, that is,  2 = 0,  1 ̸ = 0 and  1 = 0,  2 ̸ = 0. Firstly, we consider the local and global stability of  2 for the first case, and we have the following results.Theorem 6.If  2 = 0,  1 ̸ = 0 and  0 > 1 + /, then the CTL-present infection equilibrium  2 is locally asymptotically stable.
Proof.At equilibrium  2 , the characteristic equation for the corresponding linearized system of ( 2) is where  = /( + ).Further let  2 = 0; then (32) becomes By the continuous dependence of roots of the characteristic equation on  0 , we know that the curve of the roots must cross the imaginary axis as  0 decreases sufficiently close to 1.That is, the characteristic equation (33) has a pure imaginary root  =  0 ( 0 > 0) if and only if the following statement is true: We claim that the following inequality holds: In fact, we have It follows from | 0 +  + V * | ≥ | 0 + |, | 0 + | ≥ , and the inequality (35) that the modulus of the left-hand side of (34) is greater than the modulus of the right-hand side.This leads to a contradiction.Therefore, we conclude that (33) does not have any root with nonnegative real part.Thus, the CTL-present infection equilibrium  2 of system (2) is locally asymptotically stable when  0 > 1 + / in the case of  2 = 0 and  1 ̸ = 0.
The following discussions focus on the stability of the equilibrium  2 in the second case.Let  1 = 0 in (32); it follows that that where  1 = 0.By direct calculation we can get CTLpresent infection equilibrium  2 = (210.5263,2.0000, 300.0000, 306.5395) for system (50).

Conclusions
In this paper, we have discussed HIV infection model with intracellular delay and CTL-response delay.We assume that the production of CTLs depends on the infected cells and CTL cells for some important biological meanings.Dynamical analysis of system (2) shows that intracellular delay  1 and immune delay  2 play different roles in the stability of the equilibrium.The results show that when  0 < 1, the infection-free equilibrium is globally asymptotically stable, which means that the viruses are cleared and immune is not active.When 1 <  0 < 1 + /, the CTL-absent infection equilibrium exists and is globally asymptotically stable, which means that the CTL immune response would not be activated and viral infection becomes vanished.When  0 > 1 + / and  2 = 0, the CTL-present infection equilibrium is globally asymptotically stable.Actually, the intracellular delay does not affect the stability of the system.When  0 > 1 + / and  1 = 0, system (2) may undergo a stability switch.

Disclosure
The authors declare that they have no financial or personal relationships with other people or organizations that can inappropriately influence their work; there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the paper.

Figure 3 :
Figure 3: The time histories and the phase trajectories of the system (2) after Hopf bifurcation occurs for  2 = 2.55.