
This work focuses on an HIV infection model with intracellular delay and immune response delay, in which the former delay refers to the time it takes for healthy cells to become infectious after infection, and the latter delay refers to the time when immune cells are activated and induced by infected cells. By investigating the properties of the associated characteristic equation, we derive sufficient criteria for the asymptotic stability of the equilibria and the existence of Hopf bifurcation to the delayed model. Based on normal form theory and center manifold theorem, the stability and the direction of the Hopf bifurcating periodic solutions are studied. The results reveal that the intracellular delay cannot affect the stability of the immunity-present equilibrium, but the immune response delay can destabilize the stable immunity-present equilibrium through the Hopf bifurcation. Numerical simulations are provided to support the theoretical results.
Citation: Yu Yang, Gang Huang, Yueping Dong. Stability and Hopf bifurcation of an HIV infection model with two time delays[J]. Mathematical Biosciences and Engineering, 2023, 20(2): 1938-1959. doi: 10.3934/mbe.2023089
[1] | Yan Wang, Minmin Lu, Daqing Jiang . Viral dynamics of a latent HIV infection model with Beddington-DeAngelis incidence function, B-cell immune response and multiple delays. Mathematical Biosciences and Engineering, 2021, 18(1): 274-299. doi: 10.3934/mbe.2021014 |
[2] | Jinhu Xu, Yicang Zhou . Bifurcation analysis of HIV-1 infection model with cell-to-cell transmission and immune response delay. Mathematical Biosciences and Engineering, 2016, 13(2): 343-367. doi: 10.3934/mbe.2015006 |
[3] | Juan Wang, Chunyang Qin, Yuming Chen, Xia Wang . Hopf bifurcation in a CTL-inclusive HIV-1 infection model with two time delays. Mathematical Biosciences and Engineering, 2019, 16(4): 2587-2612. doi: 10.3934/mbe.2019130 |
[4] | Xuejuan Lu, Lulu Hui, Shengqiang Liu, Jia Li . A mathematical model of HTLV-I infection with two time delays. Mathematical Biosciences and Engineering, 2015, 12(3): 431-449. doi: 10.3934/mbe.2015.12.431 |
[5] | Jiawei Deng, Ping Jiang, Hongying Shu . Viral infection dynamics with mitosis, intracellular delays and immune response. Mathematical Biosciences and Engineering, 2023, 20(2): 2937-2963. doi: 10.3934/mbe.2023139 |
[6] | Haitao Song, Weihua Jiang, Shengqiang Liu . Virus dynamics model with intracellular delays and immune response. Mathematical Biosciences and Engineering, 2015, 12(1): 185-208. doi: 10.3934/mbe.2015.12.185 |
[7] | Ning Bai, Rui Xu . Mathematical analysis of an HIV model with latent reservoir, delayed CTL immune response and immune impairment. Mathematical Biosciences and Engineering, 2021, 18(2): 1689-1707. doi: 10.3934/mbe.2021087 |
[8] | Huan Kong, Guohong Zhang, Kaifa Wang . Stability and Hopf bifurcation in a virus model with self-proliferation and delayed activation of immune cells. Mathematical Biosciences and Engineering, 2020, 17(5): 4384-4405. doi: 10.3934/mbe.2020242 |
[9] | Shishi Wang, Yuting Ding, Hongfan Lu, Silin Gong . Stability and bifurcation analysis of $ SIQR $ for the COVID-19 epidemic model with time delay. Mathematical Biosciences and Engineering, 2021, 18(5): 5505-5524. doi: 10.3934/mbe.2021278 |
[10] | Bing Li, Yuming Chen, Xuejuan Lu, Shengqiang Liu . A delayed HIV-1 model with virus waning term. Mathematical Biosciences and Engineering, 2016, 13(1): 135-157. doi: 10.3934/mbe.2016.13.135 |
This work focuses on an HIV infection model with intracellular delay and immune response delay, in which the former delay refers to the time it takes for healthy cells to become infectious after infection, and the latter delay refers to the time when immune cells are activated and induced by infected cells. By investigating the properties of the associated characteristic equation, we derive sufficient criteria for the asymptotic stability of the equilibria and the existence of Hopf bifurcation to the delayed model. Based on normal form theory and center manifold theorem, the stability and the direction of the Hopf bifurcating periodic solutions are studied. The results reveal that the intracellular delay cannot affect the stability of the immunity-present equilibrium, but the immune response delay can destabilize the stable immunity-present equilibrium through the Hopf bifurcation. Numerical simulations are provided to support the theoretical results.
It is all known that acquired immunodeficiency syndrome (AIDS), an incurable chronic infectious disease, is caused by the human immunodeficiency virus (HIV). The dynamics of HIV in a host can be broadly divided into three stages [1]. First of all, after the human body infection with HIV, CD4+T cells in the body decrease dramatically and the viral load reaches a sharp peak, which is called the acute stage. Secondly, the body is subjected to a prolonged asymptomatic phase in which the viral load slowly increases as the body's immune system works normally. Finally, the body's immune system is disrupted by HIV, resulting in death from various illnesses. In order to gain a clearer understanding of the disease and develop various drug treatments against it, several HIV models have been proposed [1,2]. The classical model of viral infection includes the interaction between four variables, namely x, y, v and z, which stand for the density of healthy target cells, infected cells, free virus particles, and cytotoxic T lymphocyte (CTL), respectively [3,4,5]. The specific ordinary differential equations form is as follows
{˙x(t)=Λ−αx(t)v(t)−dx(t),˙y(t)=αx(t)v(t)−ay(t)−py(t)z(t),˙v(t)=ky(t)−uv(t),˙z(t)=f(x,y,z)−bz(t), | (1.1) |
where new target cells are produced at a constant rate Λ and die at a rate d. And α indicates the transmission rate of viral infection. The mortality of infected cells is a. CTLs fight against infection at a rate p. k denotes the rate at which infected cell produces virus particles. u is the rate at which virus particles are removed. f(x,y,z) describes the rate of immune response activated, and b is the decay rate of the specific CTL.
Based on the biological phenomenon that the average lifetime of virus particles is usually significantly shorter than that of infected cells, Arnaout et al. [6] gave a quasi-steady-state hypothesis. The assumption shows that the viral load reaches a quasi-equilibrium level relatively quickly compared to the slow change in the level of infected cells. According to the third equation ˙v(t)=0 in the model (1.1), v(t)=ky(t)/u holds, that is, the concentration of free virus is simply proportional to the concentration of infected cells. Thus, model (1.1) can be modified to
{˙x(t)=Λ−βx(t)y(t)−dx(t),˙y(t)=βx(t)y(t)−ay(t)−py(t)z(t),˙z(t)=f(x,y,z)−bz(t), | (1.2) |
where the rates of cell infection and viral multiplication are both denoted by β=αk/u. Model (1.2) is also considered an HIV infection model involving cell-to-cell transmission [7,8]. Due to the complexity of the human immune system [3,9,10,11,12,13], several types of proliferation of the immune response function f(x,y,z) have been proposed: (i) f(x,y,z)=cy(t), CTLs are generated only by the stimulation of the levels of infected cells; (ii) f(x,y,z)=cy(t)z(t), the proliferation of CTLs is caused by the interaction between infected cells and their own cells; (iii) f(x,y,z)=cx(t)y(t)z(t), the activation and proliferation of CTLs are dependent on the levels of the three cells mentioned above, i.e., CTLs, infected cells and healthy CD4+T target cells. Here when HIV invades the body, it targets the CD4+T cells, often referred to as "helper" T cells. These cells can be considered "messengers", or the command centers of the immune system. They signal other immune cells that an invader is to be fought [14,15,16,17]. Taking form (iii) and assuming that HIV evolves toward higher replication rates, Huang et al. [18] proposed and discussed a possible mechanism that enables HIV to escape immune control. Therefore, an HIV infection model with form (iii) may lead to more meaningful and realistic results.
Indeed, when HIV invades the body, it takes time for both the infection and the immune response to occur. Time delays are often used to explain various biological transitions. The intracellular delay describes the latent period between the time when target cells are infected. Since the complexity and uncertainty of the principle by which CTLs are activated by infected cells, the immune response delay is introduced. Mathematical models of HIV infection accounting for time delays have been extensively explored [18,19,20,21,22,23,24,25,26]. Combining data from clinical experiments, Herz et al. [9] first used intracellular delay to describe the time between the initial viral entry into a target cell and subsequent viral production. Wang et al. [27] analyzed the dynamic properties of a three-dimensional delay differential equation by choosing f=cy(t−τ). Huang et al. [20] discussed CTLs immune response delay in two different situations f=cy(t−τ)z(t) and f=cy(t−τ)z(t−τ). Extending to a four-dimensional system, Zhu et al. [17] took f=cx(t−τ)y(t−τ)z(t−τ) as an example to study the influence of time delay on the system.
Motivated by the works in [17,20,21], we suppose that the specific CTL proliferates at a rate cxyz. Then two-time delays are considered in the model (1.2). To be specific, the first delay τ1 characterizes the intracellular latency for cell-to-cell infection and the second delay τ2 describes the time lag in the activation of CTLs induced by infected cells. The following delay differential equations are investigated.
{˙x(t)=Λ−βx(t)y(t)−dx(t),˙y(t)=βx(t−τ1)y(t−τ1)−ay(t)−py(t)z(t),˙z(t)=cx(t)y(t−τ2)z(t)−bz(t). | (1.3) |
The dynamics of the delay-induced system convey more intricate scenarios than the dynamics portrayed in the ODE system without delay. This paper aims to discuss the effects of time delays on the local dynamics of model (1.3), such as the effects of time delay on the steady-state and the periodic solution.
The article is arranged as follows: In Section 2, the positivity of the solution and equilibria of the model (1.3) are performed. In Section 3, we give the local stability analysis and Hopf bifurcation results. In Section 4, the normal form near the Hopf bifurcation is derived by a series of calculations. We exemplify the obtained analytical results by numerical simulations in Section 5. In Section 6, we conclude with the obtained analysis results.
From a biological model with practical implications, the non-negative initial conditions of model (1.3) need satisfy
x(θ)=ϕ1(θ),y(θ)=ϕ2(θ),z(θ)=ϕ3(θ),θ∈[−τ,0], | (2.1) |
where τ=max{τ1,τ2}, ϕ=(ϕ1,ϕ2,ϕ3)⊤∈C and C is the Banach space C([−τ,0],R3+) of all continuous functions that map from [−τ,0] into R3+. By the fundamental mathematical theory [28], the uniqueness and existence of the solution on [0,+∞) of model (1.3) with conditions (2.1) hold. In addition, we reach the following conclusion.
Theorem 2.1. Let S(t,ϕ)=(x(t,ϕ),y(t,ϕ),z(t,ϕ))⊤ be a solution of model (1.3) satisfying the initial conditions (2.1). Then S(t,ϕ) is non-negative.
Proof. Using the method in [29,30], we can rewrite model (1.3) as
˙S(t)=F(St), |
where St(θ)=S(t+θ) for θ∈[−τ,0] and
F(ϕ)=(Λ−βϕ1(0)ϕ2(0)−dϕ1(0)βϕ1(−τ1)ϕ2(−τ1)−aϕ2(0)−pϕ2(0)ϕ3(0)cϕ1(0)ϕ2(−τ2)ϕ3(0)−bϕ3(0)) |
for ϕ=(ϕ1,ϕ2,ϕ3)⊤∈C. Clearly for any ϕ∈C, ϕi(0)=0, i=1,2,3, we can prove Fi(ϕ)≥0. Then, on the basis of Theorem 2.1 in [29], it can be deduced that S(t,ϕ)≥0 for all t≥0.
For the convenience of discussion, we apply the following notation in [18] to model (1.3)
R0=Λβad,Q0=cΛbβR0−1R0. |
Here, R0 and Q0 are denoted as the basic reproduction number of infected cells and immune response. The dynamic properties of model (1.3) without time delays are mainly determined by these two threshold parameters, such as the existence and stability of equilibria. Below we give the results already discussed in [18].
Lemma 2.1. For model (1.3) with τ1=0 and τ2=0.
(i) There is always an infection-free equilibrium E0=(x0,y0,z0), where
x0=Λd,y0=z0=0. |
When R0<1, E0 is the unique equilibrium and stable.
(ii) When R0>1, the system also has an immunity-absent equilibrium E1=(x1,y1,z1), which is stable if Q0<1, where
x1=aβ,y1=dβ(R0−1),z1=0. |
(iii) When Q0>1, an immunity-present equilibrium E∗=(x∗,y∗,z∗) exists and is stable, where
x∗=cΛ−bβcd=bβcd(Q0−1+Q0R0−1),y∗=bcx∗=bdcΛ−bβ=dβ(Q0−1+Q0R0−1)−1,z∗=bβ2cdp(Q0−1). |
This section mainly focuses on the effects of time delays on the local stability of the model (1.3) at the equilibrium. By linearizing model (1.3), we obtain the characteristic equation at the equilibrium E∗(x∗,y∗,z∗). The corresponding characteristic equation is as follows
det(λ+d+βy∗βx∗0−βy∗e−λτ1λ−βx∗e−λτ1+a+pz∗py∗−cy∗z∗−cx∗z∗e−λτ2λ−cx∗y∗+b)=0. | (3.1) |
From the above expression (3.1), the stability results for equilibria E0 and E1 can be given as follows.
Theorem 3.1. Consider model (1.3) for any τ1≥0 and τ2≥0.
(i) The infection-free equilibrium E0 is locally asymptotically stable if R0<1 and unstable if R0>1. When R0=1, model (1.3) undergoes a fold bifurcation at E0.
(ii) When the immunity-absent equilibrium E1 exists, it is locally asymptotically stable if Q0<1 and unstable if Q0>1.
Proof. (i) At E0=(x0,y0,z0), the characteristic equation (3.1) turns into
(λ+b)(λ+d)(λ+a−βx0e−λτ1)=0, | (3.2) |
and it has roots λ=−b<0, λ=−d<0 and remaining root will be executed from
λ+a=βx0e−λτ1. | (3.3) |
We assume that λ has non-negative real parts, then take the modulus of both sides of Eq (3.3) so that the left-hand side becomes
|λ+a|≥a, |
but the right-hand side of Eq (3.3) when R0<1 becomes
|βx0e−λτ1|≤βx0<a. |
There is a contradiction. Hence λ has no non-negative real parts. Since λ=0 is not the root of Eq (3.3) when R0<1, then all the roots of the characteristic equation of E0 have negative real parts. Therefore, E0 is locally asymptotically stable if R0<1. When R0=1, the characteristic equation (3.2) has a zero root λ=0, and
dλdβ|R0=1=x0e−λτ11+βx0τ1e−λτ1>0. |
Therefore, model (1.3) undergoes a fold bifurcation at E0. Besides, Eq (3.3) is equivalent to
h(λ)=λ+a−βx0e−λτ1=0. |
Thus, h(0)=a−βx0<0 when R0>1, and limλ→+∞h(λ)=+∞. This yields that Eq (3.3) has at least one positive root, which implies that E0 is unstable if R0>1.
(ii) At E1=(x1,y1,z1), the characteristic equation (3.1) turns into
(λ−cx1y1+b)((λ+a)(λ+d+βy1)−βx1(λ+d)e−λτ1)=0. |
Obviously, it has an eigenvalue λ=cx1y1−b=b(Q0−1). If Q0>1, λ>0 holds which indicates that E1 is unstable. If Q0<1, we have λ<0. Next, we analyze the transcendental equation
(λ+a)(λ+d+βy1)=βx1(λ+d)e−λτ1. | (3.4) |
Clearly, λ=0 is not the root of Eq (3.4). Using the same method as above, suppose the real part of λ is positive. Then
|(λ+a)(λ+d+βy1)|>|λ+a||λ+d|>a|λ+d|, |
however,
|βx1(λ+d)e−λτ1|≤βx1|λ+d|=a|λ+d|. |
The occurrence of the contradiction illustrates that the real parts of λ is negative. Thus, E1 is locally asymptotically stable when R0>1 and Q0<1.
In the following contents, the effect of τ1 and τ2 on the existence of local Hopf bifurcation of model (1.3) in the immunity-present equilibrium E∗ will be described in detail. To simplify the analysis, let X=x(t)−x∗, Y=y(t)−y∗, Z=z(t)−z∗, model (1.3) turns into
{˙X(t)=a11X(t)+a12Y(t)+F1,˙Y(t)=a22Y(t)+a23Z(t)+b21X(t−τ1)+b22Y(t−τ1)+F2,˙Z(t)=a31X(t)+c32Y(t−τ2)+F3. |
where
a11=−d−βy∗,a12=−βx∗,a22=−a−pz∗,a23=−py∗,a31=cy∗z∗,b21=βy∗,b22=βx∗,c32=cx∗z∗,F1=−βX(t)Y(t),F2=−pY(t)Z(t)+βX(t−τ1)Y(t−τ1),F3=cy∗X(t)Z(t)+cz∗X(t)Y(t−τ2)+cx∗Y(t−τ2)Z(t)+cX(t)Y(t−τ2)Z(t). |
The linearized part is given separately,
{˙X(t)=a11X(t)+a12Y(t),˙Y(t)=a22Y(t)+a23Z(t)+b21X(t−τ1)+b22Y(t−τ1),˙Z(t)=a31X(t)+c32Y(t−τ2). | (3.5) |
Then, related characteristic equation of model (3.5) can be expressed as
λ3+A1λ2+A2λ+A3+(B1λ2+B2λ)e−λτ1+(C1λ+C2)e−λτ2=0, | (3.6) |
where A1=−a11−a22, A2=a11a22, A3=−a12a23a31, B1=−b22, B2=a11b22−a12b21, C1=−a23c32, C2=a11a23c32. For τ1,τ2≥0, we will classify four cases to discuss the stability of E∗ respectively.
Case Ⅰ: τ1=τ2=0.
Equation (3.6) becomes
λ3+A11λ2+A12λ+A13=0, | (3.7) |
where A11=d+βy∗>0, A12=β2x∗y∗+bpz∗>0, A13=bdpz∗>0. Since A11A12−A13=dβ2x∗y∗+βy∗(β2x∗y∗+bpz∗)>0 holds, it is proved that the real parts of all roots of Eq (3.7) are positive by the Routh-Hurwitz criterion. Then the immunity-present equilibrium E∗ is locally asymptotically stable.
Case Ⅱ: τ1>0 and τ2=0.
Equation (3.6) becomes
λ3+A21λ2+A22λ+A23+(B1λ2+B2λ)e−λτ1=0, | (3.8) |
where A21=A1, A22=A2+C1, A23=A3+C2. The stability of equilibrium may be broken by time delay [31]. We study how the stability of E∗ varies from bifurcation parameter τ1 and results in oscillation. Suppose Eq (3.8) has a pair of pure imaginary roots λ=±iω1 (ω1>0). Solving Eq (3.8) with λ=iω1 and separating the real and imaginary parts, we get
{B1ω21cos(ω1τ1)−B2ω1sin(ω1τ1)=A23−A21ω21,B1ω21sin(ω1τ1)+B2ω1cos(ω1τ1)=ω31−A22ω1. | (3.9) |
Squaring the two equations of (3.9) and then adding them together gives
ω61+D21ω41+D22ω21+D23=0, |
where D21=A221−B21−2A22, D22=A222−2A21A23−B22, D23=A223. Let h1=ω21, then
f1(h1)=h31+D21h21+D22h1+D23=0 |
and
f′1(h1)=3h21+2D21h1+D22. |
Then, the roots of f′1(h1)=0 is
h11=−D21−√D221−3D223,h12=−D21+√D221−3D223. |
Because of D23=A223>0, we understand that f′1(h1)=0 has no positive roots when Δ=D221−3D22<0. If hypothesis (H1)
D221−3D22>0,h12>0,f1(h12)≤0 |
holds, then f1(ω21)=0 has two positive roots ω211 and ω212. Let ω211<ω212 and then f′1(ω211)<0 and f′1(ω212)>0 (see [32]). From Eqs (3.9), we can deduce
τj1k=1ω1karccos((B2−A21B1)ω21k+A23B1−A22B2B21ω21k+B22)+2jπω1k,(j=0,1,2,...;k=1,2). |
Let τ10=mink=1,2{τ(0)1k}. Differentiating both sides of characteristic equation (3.8) with respect to τ1, we obtain
[dλ(τ1)dτ1]−1=3λ2+2A21λ+A22λ(B1λ2+B2λ)e−λτ1+2B1λ+B2λ(B1λ2+B2λ)−τ1λ=−3λ2+2A21λ+A22λ(λ3+A21λ2+A22λ+A23)+2B1λ+B2λ(B1λ2+B2λ)−τ1λ. |
So we know
[dReλ(τ1)dτ1]−1λ=iω10=Re[dλ(τ1)dτ1]−1λ=iω10=3ω410+(2A221−4A22)ω210+A222−2A21A23(ω310−A22ω10)2+(A23−A21ω210)2−2B21ω210+B22B21ω410+B22ω210=f′1(ω210)B21ω410+B22ω210. |
Therefore, we assume (H2)
sign[dReλ(τ1)dτ1]=sign[dReλ(τ1)dτ1]−1=signf′1(ω210)≠0. |
Theorem 3.2. For model (1.3), when τ1>0 and τ2=0, the following conclusions hold:
(i) if Δ<0, then E∗ is locally asymptotically stable for all τ1,
(ii) if hypothesis (H1,H2) are true, E∗ is locally asymptotically stable for τ1∈[0,τ10), Hopf bifurcation occurs when τ1=τ10.
Case Ⅲ: τ1=0 and τ2>0.
Equation (3.6) becomes
λ3+A31λ2+A32λ+A33+(C1λ+C2)e−λτ2=0, | (3.10) |
where A31=A1+B1, A32=A2+B2, A33=A3. We do a similar analysis with Case Ⅱ. Defining a purely imaginary root of Eq (3.10) as λ=iω2(ω2>0) and substitute it into Eq (3.10), by conventional calculation we get
ω62+D31ω42+D32ω22+D33=0, |
where D31=A231−2A32, D32=A232−2A31A33−C21, D33=A233−C22. Let h2=ω22, then
f2(h2)=h32+D31h22+D32h2+D33=0. | (3.11) |
Notice that D33=A23−C22<0, which shows that Eq (3.11) has at least one positive root.
In general, suppose that h21, h22 and h23 are the positive roots of (3.11), then ω2k=√h2k, k=1,2,3. In the same way, we obtain
τ(j)2k=1ω2karccos(C1ω42k+(A31C2−A32C1)ω22k−A33C2C21ω22k+C22)+2jπω2k,(j=0,1,2,...;k=1,2,3). |
Let τ20=mink=1,2,3{τ(0)2k}, we have
[dλ(τ2)dτ2]−1=3λ2+2A31λ+A32λ(C1λ+C2)e−λτ2+C1λ(C1λ+C2)−τ2λ=−3λ2+2A31λ+A32λ(λ3+A31λ2+A32λ+A33)+C1λ(C1λ+C2)−τ2λ. |
So
[dReλ(τ2)dτ2]−1λ=iω20=Re[dλ(τ2)dτ2]−1λ=iω20=3ω420+(2A231−4A32)ω220+A232−2A31A33(ω320−A32ω20)2+(A33−A31ω220)2−C21C21ω220+C22=f′2(ω220)C21ω220+C22. |
Thus, making the hypothesis (H3)
[dReλ(τ2)dτ2]λ=iω20=sign[dReλ(τ2)dτ2]−1λ=iω20=signf′2(ω220)≠0. |
Theorem 3.3. For model (1.3), when τ1=0 and τ2>0, if hypothesis (H3) is true, E∗ is locally asymptotically stable for τ2∈[0,τ20), Hopf bifurcation occurs when τ2=τ20.
Case Ⅳ: τ1>0 and τ2>0.
Choosing τ2 as the bifurcation parameter, we take the root of Eq (3.6) to be λ=iω∗2(ω∗2>0). According to the same computing process, it is easy to get
{C1ω∗2sin(ω∗2τ2)+C2cos(ω∗2τ2)=A1ω∗22−A3+B1ω∗22cos(ω∗2τ1)−B2ω∗2sin(ω∗2τ1),C1ω∗2cos(ω∗2τ2)−C2sin(ω∗2τ2)=ω∗23−A2ω∗2−B1ω∗22sin(ω∗2τ1)−B2ω∗2cos(ω∗2τ1). |
Based on the sum of squares of above equations, we have
D41(ω∗2)+D42(ω∗2)sin(ω∗2τ1)+D43(ω∗2)cos(ω∗2τ1)=0, | (3.12) |
where
D41(ω∗2)=ω∗26+(A21+B21−2A2)ω∗24+(A22+B22−C21−2A1A3)ω∗22+A23−C22,D42(ω∗2)=−2B1ω∗25−2A1B2ω∗23+2A2B1ω∗23+2A3B2ω∗2,D43(ω∗2)=2A1B1ω∗24−2B2ω∗24−2A3B1ω∗22+2A2B2ω∗22. |
(H4): there are finite positive roots ω∗2k,k=1,2,...,l1 for Eq (3.12). Then the critical value is shown as
τ∗2k(j)=1ω∗2karccos(F41C2+F42C1ω∗2kC21ω∗2k2+C22)+2jπω∗2k, |
where
F41=A1ω∗22−A3+B1ω∗22cos(ω∗2τ1)−B2ω∗2sin(ω∗2τ1),F42=ω∗23−A2ω∗2−B1ω∗22sin(ω∗2τ1)−B2ω∗2cos(ω∗2τ1). |
Let τ∗20=min{τ∗2k(0)}, differentiate equation (3.6) concerning τ2,
[dλdτ2]−1=3λ2+2A1λ+A2λ(C1λ+C2)e−λτ2+(−τ1B1λ2+2B1λ−τ1B2λ+B2)e−λτ1λ(C1λ+C2)e−λτ2+C1λ(C1λ+C2)−τ2λ. |
So
[dReλdτ2]−1λ=iω∗20=Re[dλdτ2]−1λ=iω∗20=I41+I42+I43C21ω∗204+C22ω∗202, |
where
I41=((2A1C1−3C2)ω∗203+A2C2ω∗20)sin(ω∗20τ2)+(3C1ω∗204+(2A1C2−A2C1)ω∗202)cos(ω∗20τ2),I42=((τ1B1C2−τ1B2C1+2B1C1)ω∗203+B2C2ω∗20)sin(ω∗20τ2−ω∗20τ1)−(τ1B1C1ω∗204+(τ1B2C2−2B1C2+B2C1)ω∗202)cos(ω∗20τ2−ω∗20τ1),I43=−C21ω∗202. |
Thus, there exists a hypothesis (H5)
sign[dReλdτ2]λ=iω∗20=sign[dReλdτ2]−1λ=iω∗20=sign(I41+I42+I43)≠0. |
Theorem 3.4. For model (1.3), when τ1>0, τ2>0, if the hypothesis (H4,H5) are true, then E∗ is locally asymptotically stable for τ2∈[0,τ∗20), Hopf bifurcation occurs when τ2=τ∗20.
From the analysis in Section 3, sufficient conditions for model (1.3) to undergo Hopf bifurcation at E∗ have been obtained. Then we will study the bifurcation properties when τ1>0 and τ2=τ∗20 by using the normal form method and center manifold theorem [33].
For the sake of discussion, suppose τ1<τ∗20, where τ2∈[0,τ∗20). Rescaling the time by t=sτ2, let τ2=τ∗20+μ, X(sτ2)=ˉX(s), Y(sτ2)=ˉY(s), Z(sτ2)=ˉZ(s). In general, redefining ˉX(s),ˉY(s),ˉZ(s) as X(t),Y(t),Z(t) and rewriting model (1.3), we get a FDE in C([−1,0],R3)
˙u(t)=Lμ(ut)+f(μ,ut), | (4.1) |
where u(t)=(X(t),Y(t),Z(t))⊤∈R3. Lμ(ϕ):C→R3 and f(μ,ut) are described respectively as
Lμ(ϕ)=(τ∗20+μ)(Aϕ(0)+Bϕ(−τ1τ∗20+μ)+Cϕ(−1)), |
where
A=(a11a1200a22a23a3100),B=(000b21b220000),C=(0000000c320), |
and
f(μ,ϕ)=(τ∗20+μ)(F1F2F3), |
where
F1=−βϕ1(0)ϕ2(0),F2=−pϕ2(0)ϕ3(0)+βϕ1(−τ1τ∗20)ϕ2(−τ1τ∗20),F3=cy∗ϕ1(0)ϕ3(0)+cz∗ϕ1(0)ϕ2(−1)+cx∗ϕ2(−1)ϕ3(0)+cϕ1(0)ϕ2(−1)ϕ3(0). |
By the Riesz representation theorem, there exists a function η(θ,μ) of bounded variation for θ∈[−1,0] such that
Lμ(ϕ)=∫0−1dη(θ,μ)ϕ(θ), |
for ϕ∈C([−1,0],R3). In fact, we can choose
η(θ,μ)={(τ∗20+μ)(A+B+C),θ=0(τ∗20+μ)(B+C),θ∈[−τ1τ∗20+μ,0)(τ∗20+μ)C,θ∈(−1,−τ1τ∗20+μ)0.θ=−1. |
For ϕ∈C([−1,0],R3), define
A(μ)ϕ(θ)={dϕ(θ)dθ,θ∈[−1,0),∫0−1dη(s,μ)ϕ(s),θ=0. |
and
R(μ)ϕ(θ)={0,θ∈[−1,0),f(μ,ϕ),θ=0. |
Then Eq (4.1) turns into
˙ut=A(μ)ut+R(μ)ut. |
For θ∈[−1,0], ψ∈C1([−1,0],(R3)∗), define a operator
A∗ψ(s)={−dψ(s)ds,s∈(0,1],∫0−1dη⊤(t,0)ψ(−t),s=0, |
and a bilinear inner product
⟨ψ(s),ϕ(θ)⟩=ˉψ(0)ϕ(0)−∫0−1∫θξ=0ˉψ(ξ−θ)dη(θ)ϕ(ξ)dξ, |
where η(θ)=η(θ,0), A(0) and A∗ are adjoint operators. The eigenvalues of A(0) are known to be ±iω∗20τ∗20 by previous discussion which are also eigenvalues of A∗. Assume that the eigenvectors of A(0) and A∗ corresponding to the eigenvalues iω∗20τ∗20 and −iω∗20τ∗20 are q(θ)=(1,q2,q3)⊤eiω∗20τ∗20θ,θ∈[−1,0] and q∗(s)=D(1,q∗2,q∗3)⊤eiω∗20τ∗20s,s∈[0,1], respectively, such that
A(0)q(θ)=iω∗20τ∗20q(θ),A∗q∗(s)=−iω∗20τ∗20q∗(s). |
Thus, we can figure out
q2=iω∗20−a11a12,q3=a31+c32q2e−iω∗20τ∗20iω∗20,q∗2=ia11ω∗20−ω∗202a23a31−ib21ω∗20eiω∗20τ1,q∗3=−a23q∗2iω∗20. |
From ⟨q∗(s),q(θ)⟩=1, ⟨q∗(s),ˉq(θ)⟩=0, we have
⟨q∗(s),q(θ)⟩=ˉq∗(0)⋅q(0)−∫0−1∫θξ=0ˉq∗⊤(ξ−θ)dη(θ)q(ξ)dξ=ˉD(1,ˉq∗2,ˉq∗3)(1,q2,q3)⊤−∫0−1∫θξ=0ˉD(1,ˉq∗2,ˉq∗3)e−iω∗20τ∗20(ξ−θ)dη(θ)(1q2q3)eiω∗20τ∗20ξdξ=ˉD(1+q2ˉq∗2+q3ˉq∗3)−ˉq∗⊤(0)∫0−1∫θξ=0eiω∗20τ∗20θdξdη(θ)q(0)=ˉD(1+q2ˉq∗2+q3ˉq∗3+ˉq∗2(b21+b22q2)τ1e−iω∗20τ1+c32q2ˉq∗3τ∗20e−iω∗20τ∗20). |
Hence, ˉD−1=1+q2ˉq∗2+q3ˉq∗3+ˉq∗2(b21+b22q2)τ1e−iω∗20τ1+c32q2ˉq∗3τ∗20e−iω∗20τ∗20.
Next, we compute the center manifold C0 at μ=0. Let ut be the solution of Eq (4.1), define
m(t)=⟨q∗,ut⟩,W(t,θ)=ut(θ)−m(t)q(θ)−ˉm(t)ˉq(θ)=ut(θ)−2Re(m(t)q(θ)). |
On the center manifold C0, we have
W(t,θ)=W(m,ˉm,θ)=W20(θ)m22+W11(θ)mˉm+W02(θ)ˉm22+⋯, | (4.2) |
where m,ˉm are local coordinates for center manifold C0 in the direction of q∗ and ˉq∗. For the solution ut∈C0 of (4.1), there exists ⟨ψ,Aϕ⟩=⟨A∗ψ,ϕ⟩ when μ=0, we get
˙m(t)=⟨q∗,A(0)ut⟩+⟨q∗,R(0)ut⟩=⟨A∗q∗,ut⟩+⟨q∗,f(0,W(m,ˉm,θ)+2Re(m(t)q(θ)))⟩=iω∗20τ∗20m(t)+ˉq∗(0)f(0,W(m,ˉm,θ)+2Re(m(t)q(0)))=:iω∗20τ∗20m(t)+ˉq∗(0)f0(m,ˉm). |
The above equation is equivalent to
˙m(t)=iω∗20τ∗20m(t)+g(m,ˉm), |
where
g(m,ˉm)=ˉq∗(0)f0(m,ˉm)=g20m22+g11mˉm+g02ˉm22+g21m2ˉm2!+⋯, | (4.3) |
then
g(m,ˉm)=ˉq∗(0)f0(m,ˉm)=ˉDτ∗20(1,ˉq∗2,ˉq∗3)(F1,F2,F3)⊤. | (4.4) |
Defining
ut(θ)=(u1t(θ),u2t(θ),u3t(θ))⊤=W(t,θ)+mq(θ)+ˉmˉq(θ),q(θ)=(q(1)(θ),q(2)(θ),q(3)(θ))⊤=(1,q2,q3)⊤eiω∗20τ∗20θ, |
we have
u1t(0)=m+ˉm+W(1)20(0)m22+W(1)11(0)mˉm+W(1)02(0)ˉm22+O(|(m,ˉm)|3),u2t(0)=q2m+ˉq2ˉm+W(2)20(0)m22+W(2)11(0)mˉm+W(2)02(0)ˉm22+O(|(m,ˉm)|3),u3t(0)=q3m+ˉq3ˉm+W(3)20(0)m22+W(3)11(0)mˉm+W(3)02(0)ˉm22+O(|(m,ˉm)|3), |
u1t(−τ1τ∗20)=me−iω∗20τ1+ˉmeiω∗20τ1+W(1)20(−τ1τ∗20)m22+W(1)11(−τ1τ∗20)mˉm+W(1)02(−τ1τ∗20)ˉm22+O(|(m,ˉm)|3),u2t(−τ1τ∗20)=q2me−iω∗20τ1+ˉq2ˉmeiω∗20τ1+W(2)20(−τ1τ∗20)m22+W(2)11(−τ1τ∗20)mˉm+W(2)02(−τ1τ∗20)ˉm22+O(|(m,ˉm)|3),u3t(−τ1τ∗20)=q3me−iω∗20τ1+ˉq3ˉmeiω∗20τ1+W(3)20(−τ1τ∗20)m22+W(3)11(−τ1τ∗20)mˉm+W(3)02(−τ1τ∗20)ˉm22+O(|(m,ˉm)|3), |
u1t(−1)=me−iω∗20τ∗20+ˉmeiω∗20τ∗20+W(1)20(−1)m22+W(1)11(−1)mˉm+W(1)02(−1)ˉm22+O(|(m,ˉm)|3),u2t(−1)=q2me−iω∗20τ∗20+ˉq2ˉmeiω∗20τ∗20+W(2)20(−1)m22+W(2)11(−1)mˉm+W(2)02(−1)ˉm22+O(|(m,ˉm)|3)u3t(−1)=q3me−iω∗20τ∗20+ˉq3ˉmeiω∗20τ∗20+W(3)20(−1)m22+W(3)11(−1)mˉm+W(3)02(−1)ˉm22+O(|(m,ˉm)|3). |
Combining (4.3) with (4.4), we obtain
g(m,ˉm)=ˉDτ∗20(1,ˉq∗2,ˉq3∗)×(J11m2+J12mˉm+J13ˉm2+J14m2ˉmJ21m2+J22mˉm+J23ˉm2+J24m2ˉmJ31m2+J32mˉm+J33ˉm2+J34m2ˉm)+⋯, |
where
J11=−βq(2)(0),J12=−β(q(2)(0)+ˉq(2)(0)),J13=−βˉq(2)(0),J14=−β(12ˉq(2)(0)W(1)20(0)+q(2)(0)W(1)11(0)+12W(2)20(0)+W(2)11(0)),J21=−pq(2)(0)q(3)(0)+βq(1)(−τ1τ∗20)q(2)(−τ1τ∗20),J22=−p(ˉq(2)(0)q(3)(0)+q(2)(0)ˉq(3)(0))+β(ˉq(1)(−τ1τ∗20)q(2)(−τ1τ∗20)+q(1)(−τ1τ∗20)ˉq(2)(−τ1τ∗20)),J23=−pˉq(2)(0)ˉq(3)(0)+βˉq(1)(−τ1τ∗20)ˉq(2)(−τ1τ∗20),J24=−p(12ˉq(2)(0)W(3)20(0)+q(2)(0)W(3)11(0)+12ˉq(3)(0)W(2)20(0)+q(3)(0)W(2)11(0))+β(12ˉq(1)(−τ1τ∗20)W(2)20(−τ1τ∗20)+q(1)(−τ1τ∗20)W(2)11(−τ1τ∗20))+β(12ˉq(2)(−τ1τ∗20)W(1)20(−τ1τ∗20)+q(2)(−τ1τ∗20)W(1)11(−τ1τ∗20)),J31=cy∗q(3)(0)+cz∗q(2)(−1)+cx∗q(2)(−1)q(3)(0),J32=cy∗(q(3)(0)+ˉq(3)(0))+cz∗(q(2)(−1)+ˉq(2)(−1))+cx∗(ˉq(2)(−1)q(3)(0)+q(2)(−1)ˉq(3)(0)),J33=cy∗ˉq(3)(0)+cz∗ˉq(2)(−1)+cx∗ˉq(2)(−1)ˉq(3)(0),J34=cy∗(12ˉq(3)(0)W(1)20(0)+q(3)(0)W(1)11(0)+12W(3)20(0)+W(3)11(0))+cz∗(12ˉq(2)(−1)W(1)20(0)+q(2)(−1)W(1)11(0)+12W(2)20(−1)+W(2)11(−1))+cx∗(12ˉq(2)(−1)W(3)20(0)+q(2)(−1)W(3)11(0)+12ˉq(3)(0)W(2)20(−1)+q(3)(0)W(2)11(−1))+c(ˉq(2)(−1)q(3)(0)+q(2)(−1)(q(3)(0)+ˉq(3)(0))). |
Comparing the coefficient with Eq (4.3), we have
g20=2τ∗20ˉD(J11+ˉq∗2J21+ˉq∗3J31),g11=τ∗20ˉD(J12+ˉq∗2J22+ˉq∗3J32),g02=2τ∗20ˉD(J13+ˉq∗2J23+ˉq∗3J33),g21=2τ∗20ˉD(J14+ˉq∗2J24+ˉq∗3J34), | (4.5) |
with
W20(θ)=ig20w∗20τ∗20q(0)eiθw∗20τ∗20+iˉg023w∗20τ∗20ˉq(0)e−iθw∗20τ∗20+G1e2iθw∗20τ∗20,W11(θ)=−ig11w∗20τ∗20q(0)eiθw∗20τ∗20+iˉg11w∗20τ∗20ˉq(0)e−iθw∗20τ∗20+G2, |
where G1 and G2 are governed by
(2iw∗20−a11−a120−b21e−2iw∗20τ12iw∗20−a22−b22e−2iw∗20τ1−a23−a31−c32e−2iw∗20τ∗202iw∗20)G1=2(J11J12J13), |
and
(a11a120b21a22+b22a23a31c320)G2=−(J12J22J32). |
After the above analysis, the explicit expression of Eq (4.5) can be evaluated. Then, it is easy to acquire the following critical values:
C1(0)=i2τ∗20w∗20(g11g20−2|g11|2−|g02|23)+g212,μ2=−Re(C1(0))Re(λ′(τ∗20)),β2=2Re(C1(0)),T2=−ImC1(0)+μ2Imλ′(τ∗20)w∗20τ∗20. |
By the classical bifurcation theorem [33], we can state the following theorem:
Theorem 4.1. (i) μ2 determines the direction of Hopf bifurcation, if μ2>0(<0), then Hopf bifurcation is supercritical (subcritical), and the bifurcating periodic orbits of model (1.3) at E∗ exist for τ2>τ∗20,
(ii) β2 determines the stability of the bifurcating periodic orbits, if β2<0(>0), then the bifurcating periodic orbits are stable (unstable),
(iii) T2 determines the period of bifurcating periodic solution, if T2>0(<0), the period of bifurcating periodic solution increases (decreases).
In this section, we perform some numerical simulations of model (1.3) to validate our analytical results with some fixed parameters. For the set of parameter values: Λ=1.35,β=0.25,d=0.25,a=0.45,p=0.02,c=0.15,b=0.45, we can calculate R0=3>1 and Q0=1.2>1. Then model (1.3) has a unique equilibrium E∗=(2.4,1.25,7.5).
Following the calculation process shown in [34,35], we can denote Ω as the set with complex conjugate roots. Then we establish
F(ω)=||P0(iω)|2+|P1(iω)|2−|P2(iω)|2|2−4|P0(iω)¯P1(iω)|2, |
where P0(λ)=λ3+A1λ2+A2λ+A3, P1(λ)=B1λ2+B2λ, P2(λ)=C1λ+C2 and ¯P1 is the conjugate of P1. Through simulations, there exist two positive roots for F(ω)=0, namely ω−≈0.0527238 and ω+≈0.1435193 (see Figure 1(a)). Then, we obtain Ω=[0.0527238,0.1435193]. Figure 1(b)) illustrates the stability switching curves T in the crossing set Ω.
In Case Ⅰ, E∗ is locally asymptotically stable for τ1=τ2=0 (see Figure 2).
In Case Ⅱ, fixed τ2=0, then Δ=−0.2739636<0, the condition that Hopf bifurcation appears is not satisfied. As shown in Figure 1(b)), no curve intersects the horizontal axis, that is, the length of the τ1 does not change the dynamical properties of the model (1.3) and E∗ is stable for all τ1≥0. Below, we take τ1=10 and τ1=30 as examples respectively to give the solution curves of the model (1.3) (see Figure 3).
In Case Ⅲ, fixed τ1=0, we get ω20=0.0185994, τ20=6.3676306 and f′2(ω220)=0.0531887>0, then the transversality condition for Hopf bifurcation is satisfied. Figure 4 illustrates when τ2=5<τ20, E∗ is locally asymptotically stable. Figure 5 illustrates when τ2=7>τ20, Hopf bifurcation occurs and period orbit bifurcated from E∗.
In Case Ⅳ, fixed τ1=6.2, the crucial values for Hopf bifurcation are ω∗20=0.0946198, τ∗20=6.3793047 and I41+I42+I43=0.0011718>0, then the transversality condition for Hopf bifurcation is satisfied. So when τ2=5<τ∗20, E∗ is locally asymptotically stable; when τ2=7>τ∗20, Hopf bifurcation occurs and period orbit bifurcated from E∗ (see Figures 6 and 7). Furthermore, we compute μ2=−93.4286070<0, β2=1.6297392>0, T2=−1.8245185<0. So the Hopf bifurcation is subcritical, the bifurcating periodic solution is unstable and the period of the bifurcating periodic solution decreases. Besides, Figure 8 illustrates an irregular periodic oscillation of model (1.3) when τ1=86.81 and τ2=6.9.
In this paper, we have studied an HIV infection model with intracellular delay and immune response delay. The intracellular delay τ1 describes the intracellular latency for cell-to-cell infection. Since the antigenic stimulation generating CTLs may require a time lag, we assume that CTLs produced at time t depends on the number of infected cells at time t−τ2 and uninfected cells and CTLs at time t. For time delays τ1≥0 and τ2≥0, when R0<1, the infection-free equilibrium E0 is locally asymptotically stable; when R0>1 and Q0<1, the immunity-absent equilibrium E1 is locally asymptotically stable. That is, time delays τ1 and τ2 have no effect on the stability of the infection-free equilibrium E0 and immunity-absent equilibrium E1. If Q0>1, model (1.3) has an immunity-present equilibrium E∗. In Case Ⅰ, we know that without time delays, E∗ is stable. In Case Ⅱ, by numerical simulation, we find that E∗ is locally asymptotically stable for τ1>0. In Case Ⅲ, only one delay τ2 exists, when τ2 is sufficiently small, E∗ is stable, but the periodic solution is bifurcated from E∗ when the delay crosses the critical value. In Case Ⅳ, two delays coexist, restricting time delay τ1, we conclude that when τ2 is within a certain range, E∗ is stable, but the periodic solution is bifurcated from E∗ when the delay crosses the critical value. The direction and stability are discussed by the center manifold and normal form in Case Ⅳ. By comparing the four cases, it is concluded that only considering intracellular delay τ1 will not change the dynamic behavior of the model (1.3), but introducing immune response delay τ2 will break the stability of the positive equilibrium of the model (1.3) and cause population oscillations.
In fact, depending on the biological phenomena, it is also very interesting to introduce spatial heterogeneity in the model (1.3) or consider a nonautonomous model with drug therapy. Some recent research work suggests that more complex or meaningful dynamical properties may arise for partial differential equations [36,37,38]. Therefore, we will expand model (1.3) according to the actual situation and leave it for our further research work.
We thank the editor and the referees for their exceptionally helpful comments during the review process. This work is partially supported by the Fundamental Research Funds for the Central Universities, China University of Geosciences (Wuhan) (CUGSX01).
The authors declare there is no conflict of interest.
[1] |
E. A. Hernandez-Vargas, R. H. Middleton, Modeling the three stages in HIV infection, J. Theor. Biol., 320 (2013), 33–40. https://doi.org/10.1016/j.jtbi.2012.11.028 doi: 10.1016/j.jtbi.2012.11.028
![]() |
[2] |
K. A. Lythgoe, L. Pellis, C. Fraser, Is HIV short-sighted? Insights from a multistrain nested model, Evolution, 67 (2013), 2769–2782. https://doi.org/10.1111/evo.12166 doi: 10.1111/evo.12166
![]() |
[3] |
M. A. Nowak, C. R. M. Bangham, Population dynamics of immune responses to persistent viruses, Science, 272 (1996), 74–79. https://doi.org/10.1126/science.272.5258.74 doi: 10.1126/science.272.5258.74
![]() |
[4] |
M. A. Nowak, R. M. May, K. Sigmund, Immune responses against multiple epitopes, J. Theor. Biol., 175 (1995), 325–353. https://doi.org/10.1006/jtbi.1995.0146 doi: 10.1006/jtbi.1995.0146
![]() |
[5] | M. A. Nowak, R. M. May, Virus Dynamics, Oxford University Press, Oxford, 2000. |
[6] |
R. A. Arnaout, M. A. Nowak, D. Wodarz, HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing, Proc. Biol. Sci., 267 (2000), 1347–1354. https://doi.org/10.1098/rspb.2000.1149 doi: 10.1098/rspb.2000.1149
![]() |
[7] |
X. Lai, X. Zou, Modeling cell-to-cell spread of HIV-1 with logistic target cell growth, J. Math. Anal. Appl., 426 (2015), 563–584. https://doi.org/10.1016/j.jmaa.2014.10.086 doi: 10.1016/j.jmaa.2014.10.086
![]() |
[8] |
Y. Yang, L. Zou, S. Ruan, Global dynamics of a delayed within-host viral infection model with both virus-to-cell and cell-to-cell transmissions, Math. Biosci., 270 (2015), 183–191. https://doi.org/10.1016/j.mbs.2015.05.001 doi: 10.1016/j.mbs.2015.05.001
![]() |
[9] |
A. V. Herz, S. Bonhoeffer, R. M. Anderson, R. M. May, M. A. Nowak, Viral dynamics in vivo: limitations on estimations on intracellular delay and virus decay, Proc. Natl. Acad. Sci., 93 (1996), 7247–7251. https://doi.org/10.1073/pnas.93.14.7247 doi: 10.1073/pnas.93.14.7247
![]() |
[10] |
G. Huang, Y. Takeuchi, W. Ma, Lyapunov functionals for delay differential equations model of viral infections, SIAM J. Appl. Math., 70 (2010), 2693–2708. https://doi.org/10.1137/090780821 doi: 10.1137/090780821
![]() |
[11] |
Y. Jiang, T. Zhang, Global stability of a cytokine-enhanced viral infection model with nonlinear incidence rate and time delays, Appl. Math. Lett., 132 (2022), 108110. https://doi.org/10.1016/j.aml.2022.108110 doi: 10.1016/j.aml.2022.108110
![]() |
[12] |
J. Wang, H. Shi, L. Xu, L. Zang, Hopf bifurcation and chaos of tumor-Lymphatic model with two time delays, Chaos Solitons Fractals, 157 (2022), 111922. https://doi.org/10.1016/j.chaos.2022.111922 doi: 10.1016/j.chaos.2022.111922
![]() |
[13] |
K. Wang, W. Wang, X. Liu, Global stability in a viral infection model with lytic and nonlytic immune responses, Comput. Math. Appl., 51 (2006), 1593–1610. https://doi.org/10.1016/j.camwa.2005.07.020 doi: 10.1016/j.camwa.2005.07.020
![]() |
[14] |
P. Borrow, A. Tishon, S. Lee, J. Xu, I. S. Grewal, M. B. Oldstone, et al., CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response, J. Exp. Med., 183 (1996), 2129–2142. https://doi.org/10.1084/jem.183.5.2129 doi: 10.1084/jem.183.5.2129
![]() |
[15] |
R. V. Culshaw, S. Ruan, R. J. Spiteri, Optimal HIV treatment by maximising immune response, J. Math. Biol., 48 (2004), 545–562. https://doi.org/10.1007/s00285-003-0245-3 doi: 10.1007/s00285-003-0245-3
![]() |
[16] | A. R. Thomsen, A. Nansen, J. P. Christensen, S. O. Andreasen, O. Marker, CD40 ligand is pivotal to efficient control of virus replication in mice infected with lymphocytic choriomeningitis virus, J. Immunol., 161 (1998), 4583–4590. |
[17] |
H. Zhu, Y. Luo, M. Chen, Stability and Hopf bifurcation of a HIV infection model with CTL-response delay, Comput. Math. Appl., 62 (2011), 3091–3102. https://doi.org/10.1016/j.camwa.2011.08.022 doi: 10.1016/j.camwa.2011.08.022
![]() |
[18] |
G. Huang, Y. Takeuchi, A. Korobeinikov, HIV evolution and progression of the infection to AIDS, J. Theor. Biol., 307 (2012), 149–159. https://doi.org/10.1016/j.jtbi.2012.05.013 doi: 10.1016/j.jtbi.2012.05.013
![]() |
[19] |
A. M. Elaiw, A. A. Raezah, Stability of general virus dynamics models with both cellular and viral infections and delays, Math. Methods Appl. Sci., 40 (2017), 5863–5880. https://doi.org/10.1002/mma.4436 doi: 10.1002/mma.4436
![]() |
[20] |
G. Huang, H. Yokoi, Y. Takeuchi, T. Kajiwara, T. Sasaki, Impact of intracellular delay, immune activation delay andnonlinear incidence on viral dynamics, Japan. J. Indust. Appl. Math., 28 (2011), 383–411. https://doi.org/10.1007/s13160-011-0045-x doi: 10.1007/s13160-011-0045-x
![]() |
[21] |
M. L. Mann Manyombe, J. Mbang, G. Chendjou, Stability and Hopf bifurcation of a CTL-inclusive HIV-1 infection model with both viral and cellular infections, and three delays, Chaos Solitons Fractals, 144 (2021), 110695. https://doi.org/10.1016/j.chaos.2021.110695 doi: 10.1016/j.chaos.2021.110695
![]() |
[22] |
H. Miao, Z. Teng, X. Abdurahman, Stability and Hopf bifurcation for five-dimensional virus infection model with Beddington-DeAngelis incidence and three delays, J. Biol. Dyn., 12 (2018), 146–170. https://doi.org/10.1080/17513758.2017.1408861 doi: 10.1080/17513758.2017.1408861
![]() |
[23] |
H. Miao, Z. Teng, C. Kang, Stability and Hopf bifurcation of an HIV infection model with saturation incidence and two delays, Discrete Contin. Dyn. Syst. - B, 22 (2017), 2365–2387. https://doi.org/10.3934/dcdsb.2017121 doi: 10.3934/dcdsb.2017121
![]() |
[24] |
H. Shu, L. Wang, J. Watmough, Global stability of a nonlinear viral infection model with infinitely distributed intracellular delays and CTL immune responses, SIAM J. Appl. Math., 73 (2013), 1280–1302. https://doi.org/10.1137/120896463 doi: 10.1137/120896463
![]() |
[25] |
J. Wang, C. Qin, Y. Chen, X. Wang, Hopf bifurcation in a CTL-inclusive HIV-1 infection model with two time delays, Math. Biosci. Eng., 16 (2019), 2587–2612. https://doi.org/10.3934/mbe.2019130 doi: 10.3934/mbe.2019130
![]() |
[26] |
J. Xu, Y. Zhou, Bifurcation analysis of HIV-1 infection model with cell-to-cell transmission and immune response delay, Math. Biosci. Eng., 13 (2016), 343–367. https://doi.org/10.3934/mbe.2015006 doi: 10.3934/mbe.2015006
![]() |
[27] |
K. Wang, W. Wang, H. Pang, X. Liu, Complex dynamic behavior in a viral model with delayed immune response, Physica D, 226 (2007), 197–208. https://doi.org/10.1016/j.physd.2006.12.001 doi: 10.1016/j.physd.2006.12.001
![]() |
[28] | J. K. Hale, S. M. Verduyn Lunel, Introduction to Functional Differential Equations, Springer, New York, 1993. |
[29] | H. L. Smith, Monotone Dynamical Systems: An Introduction to the Theory of Competitive and Cooperative Systems, Amer. Math. Soc., Mathematical Surveys and Monographs, Providence, Rhode Island, 41 (1995). https://doi.org/10.1090/surv/041 |
[30] |
Y. Tian, Y. Yuan, Effect of time delays in an HIV virotherapy model with nonlinear incidence, Proc. Math. Phys. Eng. Sci., 472 (2016), 20150626. https://doi.org/10.1098/rspa.2015.0626 doi: 10.1098/rspa.2015.0626
![]() |
[31] | S. Ruan, J. Wei, On the zeros of a third degree exponential polynomial with applications to a delayed model for the control of testosterone secretion, IMA J. Math. Appl. Med. Biol., 18 (2001), 41–52. |
[32] |
M. Y. Li, H. Shu, Multiple stable periodic oscillations in a mathematical model of CTL response to HTLV-I infection, Bull. Math. Biol., 73 (2011), 1774–1793. https://doi.org/10.1007/s11538-010-9591-7 doi: 10.1007/s11538-010-9591-7
![]() |
[33] | B. Hassard, N. Kazarinoff, Y. Wan, Theory and Applications of Hopf Bifurcation, Cambridge University Press, Cambridge, 1981. |
[34] |
Q. An, E. Beretta, Y. Kuang, C. Wang, H. Wang, Geometric stability switch criteria in delay differential equations with two delays and delay dependent parameters, J. Differ. Equations, 266 (2019), 7073–7100. https://doi.org/10.1016/j.jde.2018.11.025 doi: 10.1016/j.jde.2018.11.025
![]() |
[35] | X. Lin, H. Wang, Stability analysis of delay differential equations with two discrete delays, Can. Appl. Math. Q., 20 (2012), 519–533. Available from: https://www.math.ualberta.ca/hwang/TwoDelayCAMQ.pdf. |
[36] |
P. Wu, Z. He, A. Khan, Dynamical analysis and optimal control of an age-since infection HIV model at individuals and population levels, Appl. Math. Modell., 106 (2022), 325–342. https://doi.org/10.1016/j.apm.2022.02.008 doi: 10.1016/j.apm.2022.02.008
![]() |
[37] |
P. Wu, H. Zhao, Mathematical analysis of an age-structured HIV/AIDS epidemic model with HAART and spatial diffusion, Nonlinear Anal. Real World Appl., 60 (2021), 103289. https://doi.org/10.1016/j.nonrwa.2021.103289 doi: 10.1016/j.nonrwa.2021.103289
![]() |
[38] |
R. Xu, C. Song, Dynamics of an HIV infection model with virus diffusion and latently infected cell activation, Nonlinear Anal. Real World Appl., 67 (2022), 103618. https://doi.org/10.1016/j.nonrwa.2022.103618 doi: 10.1016/j.nonrwa.2022.103618
![]() |
1. | Chong Chen, Zhijian Ye, Yinggao Zhou, Zhoushun Zheng, Dynamics of a delayed cytokine-enhanced diffusive HIV model with a general incidence and CTL immune response, 2023, 138, 2190-5444, 10.1140/epjp/s13360-023-04734-3 | |
2. | Liang Hong, Jie Li, Libin Rong, Xia Wang, Global dynamics of a delayed model with cytokine-enhanced viral infection and cell-to-cell transmission, 2024, 9, 2473-6988, 16280, 10.3934/math.2024788 | |
3. | Yuhua Zhang, Haiyin Li, Stability Analysis of a Mathematical Model for Adolescent Idiopathic Scoliosis from the Perspective of Physical and Health Integration, 2023, 15, 2073-8994, 1609, 10.3390/sym15081609 | |
4. | Pradeesh Murugan, Prakash Mani, Threshold dynamics of time-delay in HIV infection model with immune impairment, 2024, 0, 1937-1632, 0, 10.3934/dcdss.2024066 | |
5. | Miao Wang, Yaping Wang, Lin Hu, Linfei Nie, Analysis of a Delayed Multiscale AIDS/HIV-1 Model Coupling Between-Host and Within-Host Dynamics, 2024, 13, 2075-1680, 147, 10.3390/axioms13030147 | |
6. | Müge Meyvacı, Hopf Bifurcation Analysis of a Zika Virus Transmission Model with Two Time Delays, 2025, 8, 2636-8692, 13, 10.33187/jmsm.1607113 |