Abstract

Viral blips are a recurrent pattern observed in many persistent infections such as the human immunodeficiency virus (HIV). The main goal of this research is to present a comprehensive analytical study of a two-dimensional discrete-time in-host infection model, that exhibits viral blips, with a saturating infection rate. We examine the interactions between the population densities of infected and uninfected CD4+ T cells by discussing the model's dynamics in the long run. The local asymptotic stability of fixed points of the model is investigated. The model undergoes both flip and Neimark–Sacker bifurcations. Moreover, codimension-two bifurcations of the endemic fixed point are discussed using bifurcation theory and normal forms. The model exhibits 1:2, 1:3, and 1:4 strong resonances. Numerical simulations are performed to verify our analysis. In addition, bifurcations of higher iterations are extracted from the numerical continuation.

References

1.
Anderson
,
R. M.
,
Medley
,
G. F.
,
May
,
R. M.
, and
Johnson
,
A. M.
,
1986
, “
A Preliminary Study of the Transmission Dynamics of the Human Immunodeficiency Virus (HIV), the Causative Agent of AIDS
,”
IMA J. Math. Appl. Med. Biol.
,
3
(
4
), pp.
229
263
.10.1093/imammb/3.4.229
2.
Hernandez-Vargas
,
E. A.
, and
Middleton
,
R. H.
,
2013
, “
Modeling the Three Stages in HIV Infection
,”
J. Theor. Biol.
,
320
, pp.
33
40
.10.1016/j.jtbi.2012.11.028
3.
Jabbari
,
A.
,
Kheiri
,
H.
,
Jodayree Akbarfam
,
A.
, and
Bekir
,
A.
,
2016
, “
Dynamical Analysis of the Avian-Human Influenza Epidemic Model Using Multistage Analytical Method
,”
Int. J. Biomath.
,
9
(
6
), p.
1650090
.10.1142/S179352451650090X
4.
Mukandavire
,
Z.
,
Gumel
,
A. B.
,
Garira
,
W.
, and
Tchuenche
,
J. M.
,
2009
, “
Mathematical Analysis of a Model for HIV-Malaria Co-Infection
,”
Math. Biosci. Eng.
,
6
(
2
), pp.
333
362
.10.3934/mbe.2009.6.333
5.
Mastroberardino
,
A.
,
Cheng
,
Y.
,
Abdelrazec
,
A.
, and
Liu
,
H.
,
2015
, “
Mathematical Modeling of the HIV/AIDS Epidemic in Cuba
,”
Int. J. Biomath.
,
8
(
4
), p.
1550047
.10.1142/S1793524515500473
6.
Nikolaos
,
I. S.
,
Dietz
,
K.
, and
Schenzle
,
D.
,
1997
, “
Analysis of a Model for the Pathogenesis of AIDS
,”
Math. Biosci.
,
145
(
1
), pp.
27
46
.10.1016/S0025-5564(97)00018-7
7.
Salman
,
S. M.
,
2021
, “
Memory and Media Coverage Effect on an HIV/AIDS Epidemic Model With Treatment
,”
J. Comput. Appl. Math.
,
385
, p.
113203
.10.1016/j.cam.2020.113203
8.
Diekmann
,
O.
,
Othmer
,
H. G.
,
Planqué
,
R.
, and
Bootsma
,
M. C. J.
,
2021
, “
The Discrete-Time Kermack-McKendrick Model: A Versatile and Computationally Attractive Frame-Work for Modeling Epidemics
,”
Proc. Natl. Acad. Sci. U. S. A.
,
118
(
39
), p.
e2106332118
.10.1073/pnas.2106332118
9.
Allen
,
L. J. S.
, and
Burgin
,
A. M.
,
2000
, “
Comparison of Deterministic and Stochastic SIS and SIR Models in Discrete Time
,”
Math. Biosci.
,
163
(
1
), pp.
1
33
.10.1016/S0025-5564(99)00047-4
10.
D'Innocenzo
,
A.
,
Paladini
,
F.
, and
Renna
,
L.
,
2006
, “
A Numerical Investigation of Discrete Oscillating Epidemic Models
,”
Phys. A
,
364
, pp.
497
512
.10.1016/j.physa.2005.08.063
11.
Franke
,
J. E.
, and
Yakubu
,
A. A.
,
2006
, “
Discrete-Time SIS Epidemic Model in a Seasonal Environment
,”
SIAM J. Appl. Math.
,
66
(
5
), pp.
1563
1587
.10.1137/050638345
12.
Franke
,
J. E.
, and
Yakubu
,
A. A.
,
2008
, “
Disease-Induced Mortality in Density-Dependent Discrete-Time SIS Epidemic Models
,”
J. Math. Biol.
,
57
(
6
), pp.
755
790
.10.1007/s00285-008-0188-9
13.
Hu
,
Z.
,
Teng
,
Z.
, and
Jiang
,
H.
,
2012
, “
Stability Analysis in a Class of Discrete SIRS Epidemic Models
,”
Nonlinear Anal.: Real World Appl.
,
13
(
5
), pp.
2017
2033
.10.1016/j.nonrwa.2011.12.024
14.
Salman
,
S. M.
,
2020
, “
A Nonstandard Finite Difference Scheme and Optimal Control for an HIV Model With Beddington-DeAngelis Incidence and Cure Rate
,”
Eur. Phys. J. Plus
,
135
(
10
), p.
808
.10.1140/epjp/s13360-020-00839-1
15.
Zhang
,
D.
, and
Shi
,
B.
,
2003
, “
Oscillation and Global Asymptotic Stability in a Discrete Epidemic Model
,”
J. Math. Anal. Appl.
,
278
(
1
), pp.
194
202
.10.1016/S0022-247X(02)00717-5
16.
Culshaw
,
R. V.
, and
Ruan
,
S.
,
2000
, “
A Delay-Differential Equation Model of HIV Infection of CD4+T-Cells
,”
Math. Biosci.
,
165
(
1
), pp.
27
39
.10.1016/S0025-5564(00)00006-7
17.
Guo
,
T.
,
Qiu
,
Z.
,
Kitagawa
,
K.
,
Iwami
,
S.
, and
Rong
,
L.
,
2021
, “
Modeling HIV Multiple Infection
,”
J. Theor. Biol.
,
509
, p.
110502
.10.1016/j.jtbi.2020.110502
18.
Hillmann
,
A.
,
Crane
,
M.
, and
Ruskin
,
H. J.
,
2020
, “
Assessing the Impact of HIV Treatment Interruptions Using Stochastic Cellular Automata
,”
J. Theor. Biol.
,
502
, p.
110376
.10.1016/j.jtbi.2020.110376
19.
Yang
,
Y.
, and
Xu
,
R.
,
2022
, “
Mathematical Analysis of a Delayed HIV Infection Model With Saturated CTL Immune Response and Immune Impairment
,”
J. Appl. Math. Comput.
,
68
(
4
), pp.
2365
2380
.10.1007/s12190-021-01621-x
20.
Tarfulea
,
N.
,
2019
, “
Drug Therapy Model With Time Delays for HIV Infection With Virus-to-Cell and Cell-to-Cell Transmissions
,”
J. Appl. Math. Comput.
,
59
(
1–2
), pp.
677
691
.10.1007/s12190-018-1196-6
21.
Denu
,
D.
,
Ngoma
,
S.
, and
Salako
,
R. B.
,
2021
, “
Analysis of a Time-Delayed HIV/AIDS Epidemic Model With Education Campaigns
,”
Comput. Appl. Math.
,
40
, p.
210
.10.1007/s40314-021-01601-8
22.
Huang
,
G.
,
Takeuchi
,
Y.
, and
Ma
,
W.
,
2010
, “
Lyapunov Functionals for Delay Differential Equations Model of Viral Infections
,”
SIAM J. Appl. Math.
,
70
(
7
), pp.
2693
2708
.10.1137/090780821
23.
Pinto
,
C. M. A.
, and
Carvalho
,
A. R. M.
,
2018
, “
Fractional Dynamics of an Infection Model With Time-Varying Drug Exposure
,”
ASME J. Comput. Nonlinear Dyn.
,
13
(
9
), p.
090904
.10.1115/1.4038643
24.
Nowak
,
M. A.
, and
Bangham
,
C. R. M.
,
1996
, “
Population Dynamics of Immune Responses to Persistent Viruses
,”
Science
,
272
(
5258
), pp.
74
79
.10.1126/science.272.5258.74
25.
Rong
,
L.
,
Feng
,
Z.
, and
Perelson
,
A. S.
,
2007
, “
Emergence of HIV-1 Drug Resistance During Antiretroviral Treatment
,”
Bull. Math. Biol.
,
69
(
6
), pp.
2027
2060
.10.1007/s11538-007-9203-3
26.
Yi
,
N.
,
Liu
,
P.
, and
Zhang
,
Q.
,
2012
, “
Bifurcations Analysis and Tracking Control of an Epidemic Model With Nonlinear Incidence Rate
,”
Appl. Math. Modell.
,
36
, pp.
1033
1056
.10.1016/j.apm.2011.09.020
27.
Conway
,
J. M.
, and
Coombs
,
D.
,
2011
, “
A Stochastic Model of Latently Infected Cell Reactivation and Viral Blip Generation in Treated HIV Patients
,”
PLoS Comput. Biol.
,
7
(
4
), p.
e1002033
.10.1371/journal.pcbi.1002033
28.
Fung
,
I. C. H.
,
Gambhir
,
M.
,
van Sighem
,
A.
,
de Wolf
,
F.
, and
Garnett
,
G. P.
,
2012
, “
The Clinical Interpretation of Viral Blips in HIV Patients Receiving Antiviral Treatment: Are We Ready to Infer Poor Adherence?
,”
J. Acquired Immune Defic. Syndr.
,
60
(
1
), pp.
5
11
.10.1097/QAI.0b013e3182487a20
29.
Grennan
,
J. T.
,
Loutfy
,
M. R.
,
Su
,
D.
,
Harrigan
,
P. R.
,
Cooper
,
C.
,
Klein
,
M.
,
Machouf
,
N.
, et al.,
2012
, “
Magnitude of Virologic Blips Is Associated With a Higher Risk for Virologic Rebound in HIV-Infected Individuals: A Recurrent Events Analysis
,”
J. Infect. Dis.
,
205
(
8
), pp.
1230
1238
.10.1093/infdis/jis104
30.
Van Gaalen
,
R. D.
, and
Wahl
,
L. M.
,
2009
, “
Reconciling Conflicting Clinical Studies of Antioxidant Supplementation as HIV Therapy: A Mathematical Approach
,”
BMC Public Health
,
9
(
S1
), pp.
1
18
.10.1186/1471-2458-9-S1-S12
31.
Yao
,
W.
,
Hertel
,
L.
, and
Wahl
,
L. M.
,
2006
, “
Dynamics of Recurrent Viral Infection
,”
Proc. R. Soc. Biol. Sci.
,
273
(
1598
), pp.
2193
2199
.10.1098/rspb.2006.3563
32.
Zhang
,
W.
,
Wahl
,
L. M.
, and
Yu
,
P.
,
2014
, “
Viral Blips May Not Need a Trigger: How Transient Viremia Can Arise in Deterministic In-Host Models
,”
SIAM J. Appl. Math.
,
56
(
1
), pp.
853
881
.10.1137/130937421
33.
Yi
,
N.
,
Zhang
,
Q.
,
Liu
,
P.
, and
Lin
,
Y.
,
2011
, “
Codimension-Two Bifurcations Analysis and Tracking Control on a Discrete Epidemic Model
,”
J. Syst. Sci. Complexity
,
24
(
6
), pp.
1033
1056
.10.1007/s11424-011-9041-0
34.
Kuznetsov
,
Y. A.
,
Meijer
,
H. G. E.
, and
Veen
,
L.
,
2004
, “
The Fold-Flip Bifurcation
,”
Int. J. Bifurcation Chaos
,
14
(
07
), pp.
2253
2282
.10.1142/S0218127404010576
35.
Kuznetsov
,
Y. A.
, and
Meijer
,
H. G. E.
,
2005
, “
Numerical Normal Forms for Codim-2 Bifurcations of Fixed Points With at Most Two Critical Eigenvalues
,”
SIAM J. Sci. Comput.
,
26
(
6
), pp.
1932
1954
.10.1137/030601508
36.
Wen
,
G.
,
Wang
,
Q.
, and
Chiu
,
M.
,
2006
, “
Delay Feedback Control for Interaction of Hopf and Period Doubling Bifurcation in Discrete Systems
,”
Int. J. Bifurcation Chaos
,
16
(
1
), pp.
101
112
.10.1142/S0218127406014617
37.
Chavez
,
J. P.
,
2010
, “
Discretizing Bifurcation Diagrams Near Codimension Two Singularities
,”
Int. J. Bifurcation Chaos
,
20
(
5
), pp.
1391
1403
.10.1142/S0218127410026551
38.
Zhang
,
Y.
, and
Luo
,
G.
,
2012
, “
A Special Type of Codimension Two Bifurcation and Unusual Dynamics in a Phase-Modulated System With Switched Strategy
,”
Nonlinear Dyn.
,
67
(
4
), pp.
2727
2734
.10.1007/s11071-011-0184-2
39.
Salas
,
F.
,
Gordillo
,
F.
,
Aracil
,
J.
, and
Reginatto
,
R.
,
2008
, “
Codimension-Two Bifurcations in Indirect Field Oriented Control of Induction Motor Drives
,”
Int. J. Bifurcation Chaos
,
18
(
3
), pp.
779
792
.10.1142/S0218127408020641
40.
Chen
,
Q.
, and
Teng
,
Z.
,
2017
, “
Codimension-Two Bifurcation Analysis of a Discrete Predator-Prey Model With Nonmonotonic Functional Response
,”
J. Differ. Equations Appl.
,
23
(
12
), pp.
2093
2115
.10.1080/10236198.2017.1395418
41.
Yao
,
J.
,
Li
,
G.
, and
Guo
,
G.
,
2020
, “
Higher Codimension Bifurcation Analysis of Predator-Prey Systems With Nonmonotonic Functional Responses
,”
Int. J. Bifurcation Chaos
,
30
(
12
), p.
2050167
.10.1142/S0218127420501679
42.
Zhang
,
L.
, and
Zhang
,
C.
,
2018
, “
Codimension One and Two Bifurcations of a Discrete Stage-Structured Population Model With Self-Limitation
,”
J. Differ. Equations Appl.
,
24
(
8
), pp.
1210
1246
.10.1080/10236198.2018.1467900
43.
Alidousti
,
J.
,
Eskandari
,
Z.
,
Fardi
,
M.
, and
Asadipour
,
M.
,
2021
, “
Codimension Two Bifurcations of Discrete Bonhoeffer–van der Pol Oscillator Model
,”
Soft Comput.
,
25
(
7
), pp.
5261
5276
.10.1007/s00500-020-05524-0
44.
Salman
,
S. M.
, and
Elsadany
,
A. A.
,
2022
, “
Higher Order Codimension Bifurcations in a Discrete-Time Toxic-Phytoplankton-Zooplankton Model With Allee Effect
,”
Int. J. Nonlinear Sci. Numer. Simul.
, epub.10.1515/ijnsns-2021-0476
45.
Salman
,
S. M.
, and
Elsadany
,
A. A.
,
2023
, “
Analytical Bifurcation and Strong Resonances of a Discrete Bazykin-Berezovskaya Predator-Prey Model With Allee Effect
,”
Int. J. Biomath.
, epub.10.1142/S1793524522501364
46.
Shi
,
P. L.
, and
Dong
,
L. Z.
,
2014
, “
Dynamical Behaviors of a Discrete HIV-1 Virus Model With Bilinear Infective Rate
,”
Math. Methods Appl. Sci.
,
37
(
15
), pp.
2271
2280
.10.1002/mma.2974
47.
Ackleh
,
A. S.
,
Hossain
,
M. I.
,
Veprauskas
,
A.
, and
Zhang
,
A.
,
2019
, “
Persistence and Stability Analysis of Discrete-Time Predator-Prey Models: A Study of Population and Evolutionary Dynamics
,”
J. Differ. Equations Appl.
,
25
(
11
), pp.
1568
1603
.10.1080/10236198.2019.1669579
48.
Kuznetsov
,
Y. A.
,
1998
,
Elements of Applied Bifurcation Theory
, 2nd ed.,
Springer
,
New York
.
49.
Guckenheimer
,
J.
, and
Holmes
,
P.
,
1983
,
Nonlinear Oscillations, Dynamical Systems, and Bifurcations of Vector Fields
,
Springer-Verlag
,
New York
.
50.
Robinson
,
C.
,
1999
,
Dynamical Models, Stability, Symbolic Dynamics, and Chaos
, 2nd ed.,
CRC Press
,
London
.
51.
Zhang
,
W.
,
Wahl
,
L. M.
, and
Yu
,
P.
,
2013
, “
Conditions for Transient Viremia in Deterministic In-Host Models: Viral Blips Need No Exogenous Trigger
,”
SIAM J. Appl. Math.
,
73
(
2
), pp.
853
881
.10.1137/120884535
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