×

Incorporation of variability into the modeling of viral delays in HIV infection dynamics. (English) Zbl 1011.92037

Summary: We consider classes of functional differential equation models which arise in attempts to describe temporal delays in HIV pathogenesis. In particular, we develop methods for incorporating arbitrary variability (i.e., general probability distributions) for these delays into systems that cannot readily be reduced to a finite number of coupled ordinary differential equations (as is done in the method of stages). We discuss modeling from first principles, introduce several classes of nonlinear models (including discrete and distributed delays) and present a discussion of theoretical and computational approaches. We then use the resulting methodology to carry out simulations and perform parameter estimation calculations, fitting the models to a set of experimental data. Results obtained confirm the statistical significance of the presence of delays and the importance of including delays in validating mathematical models with experimental data. We also show that the models are quite sensitive to the mean of the distribution which describes the delay in viral production, whereas the variance of this distribution has relatively little impact.

MSC:

92C60 Medical epidemiology
34K60 Qualitative investigation and simulation of models involving functional-differential equations
92C50 Medical applications (general)
65C20 Probabilistic models, generic numerical methods in probability and statistics
Full Text: DOI

References:

[1] E. Pisani, B. Schwartländer, S. Cherney, A. Winter (Eds.), Global Summary of the HIV/AIDS Epidemic, end 1999, Joint United Nations Programme on HIV/AIDS, 2000; E. Pisani, B. Schwartländer, S. Cherney, A. Winter (Eds.), Global Summary of the HIV/AIDS Epidemic, end 1999, Joint United Nations Programme on HIV/AIDS, 2000
[2] Nelson, P. W.; Mittler, J. E.; Perelson, A. S., Effect of drug efficacy and the eclipse phase of the viral life cycle on estimates of HIV viral dynamic parameters, J. AIDS, 26, 405 (2001)
[3] M. Emerman, personal communication, Nov. 2000; M. Emerman, personal communication, Nov. 2000
[4] Mittler, J. E.; Sulzer, B.; Neumann, A. U.; Perelson, A. S., Influence of delayed viral production on viral dynamics in HIV-1 infected patients, Math. Biosci., 152, 143 (1998) · Zbl 0946.92011
[5] Holte, S.; Emerman, M., A competition model for viral inhibition of host cell proliferation, Math. Biosci., 166, 69 (2000) · Zbl 0963.92021
[6] Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J. M.; Markowitz, M., Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection, Nature, 373, 123 (1995)
[7] Perelson, A. S.; Neumann, A. U.; Markowitz, M.; Leonard, J. M.; Ho, D. D., HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time, Science, 271, 1582 (1996)
[8] Wei, X.; Ghosh, S. K.; Taylor, M. E.; Johnson, V. A.; Emini, E. A.; Deutsch, P.; Lifson, J. D.; Bonhoeffer, S.; Nowak, M. A.; Hahn, B. H.; Saag, M. S.; Shaw, G. M., Viral dynamics in human immunodeficiency virus type 1 infection, Nature, 373, 117 (1995)
[9] Mittler, J. E.; Markowitz, M.; Ho, D. D.; Perelson, A. S., Improved estimates for HIV-1 clearance rate and intracellular delay, AIDS, 13, 1415 (1999)
[10] Perelson, A. S.; Essunger, P.; Cao, Y.; Vesanen, M.; Hurley, A.; Saksela, K.; Markowitz, M.; Ho, D. D., Decay characteristics of HIV-1-infected compartments during combination therapy, Nature, 387, 188 (1997)
[11] Ramratnam, B.; Bonhoeffer, S.; Binley, J.; Hurley, A.; Zhang, L.; Mittler, J. E.; Markowitz, M.; Moore, J. P.; Perelson, A. S.; Ho, D. D., Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis, The Lancet, 354, 1782 (1999)
[12] Callaway, D. S.; Perelson, A. S., HIV-1 infection and low steady state viral loads, Bull. Math. Biol., 64, 29 (2002) · Zbl 1334.92227
[13] Kramer, I., Modeling the dynamical impact of HIV on the immune system: Viral clearance, infection, and AIDS, Math. Comput. Modell., 29, 95 (1999) · Zbl 1001.92537
[14] Monteiro, H. A.; Gonçalves, C. H.O.; Piqueira, J. R.C., A condition for successful escape of a mutant after primary HIV infection, J. Theoret. Biol., 203, 399 (2000)
[15] Murray, J. M.; Kaufmann, G.; Kelleher, A. D.; Cooper, D. A., A model of primary HIV-1 infection, Math. Biosci., 154, 57 (1998) · Zbl 0938.92020
[16] Nowak, M. A.; Bonhoeffer, S.; Shaw, G. M.; May, R. M., Anti-viral drug treatment: Dynamics of resistance in free virus and infected cell populations, J. Theor. Biol., 184, 203 (1997)
[17] Phillips, A. N., Reduction of HIV concentration during acute infection: Independence from a specific immune response, Science, 271, 497 (1996)
[18] Stafford, M. A.; Corey, L.; Cao, Y.; Daar, E. S.; Ho, D. D.; Perelson, A. S., Modeling plasma virus concentration during primary HIV infection, J. Theor. Biol., 203, 285 (2000)
[19] Wein, L. M.; D’Amato, R. M.; Perelson, A. S., Mathematical analysis of antiretroviral therapy aimed at HIV-1 eradication or maintenance of low viral loads, J. Theor. Biol., 192, 81 (1998)
[20] Wodarz, D.; Jansen, V. A.A., The role of T cell help for anti-viral CTL responses, J. Theor. Biol., 211, 419 (2001)
[21] Wodarz, D.; Lloyd, A. L.; Jansen, V. A.A.; Nowak, M. A., Dynamics of macrophage and t cell infection by HIV, J. Theor. Biol., 196, 101 (1999)
[22] Grossman, Z.; Feinberg, M.; Kuznetsov, V.; Dimitrov, D.; Paul, W., HIV infection: how effective is drug combination treatment?, Immunol. Today, 19, 528 (1998)
[23] Grossman, Z.; Polis, M.; Feinberg, M. B.; Levi, I.; Jankelevich, S.; Yarchoan, R.; Boon, J.; de Wolf, F.; Lange, J. M.A.; Goudsmit, J.; Dimitrov, D. S.; Paul, W. E., Ongoing HIV dissemination during HAART, Nature Med., 5, 1099 (1999)
[24] A.V.M. Herz, S. Bonhoeffer, R.M. Anderson, R.M. May, M.A. Nowak, Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay, Proc. Nat. Acad. Sci. USA 93 (1996) 7247-7251; A.V.M. Herz, S. Bonhoeffer, R.M. Anderson, R.M. May, M.A. Nowak, Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay, Proc. Nat. Acad. Sci. USA 93 (1996) 7247-7251
[25] Lloyd, A. L., The dependence of viral parameter estimates on the assumed viral load life cycle: limitations of studies of viral load data, Proc. Roy. Soc. Lond. B, 268, 847 (2001)
[26] Nelson, P. W.; Murray, J. D.; Perelson, A. S., A model of HIV-1 pathogenesis that includes an intracellular delay, Math. Biosci., 163, 201 (2000) · Zbl 0942.92017
[27] Nelson, P. W.; Perelson, A. S., Mathematical analysis of delay differential equation models of HIV-1 infection, Math. Biosci., 179, 73 (2002) · Zbl 0992.92035
[28] Culshaw, R. V.; Ruan, S., A delay-differential equation model of HIV infection of CD4+ T-cells, Math. Biosci., 165, 27 (2000) · Zbl 0981.92009
[29] Tam, J., Delay effect in a model for virus replication, IMA J. Math. Appl. Med. Biol., 16, 29 (1999) · Zbl 0914.92012
[30] Kamina, A.; Makuch, R. W.; Zhao, H., Stochastic modeling of early HIV-1 population dynamics, Math. Biosci., 170, 187 (2001) · Zbl 1005.92019
[31] Tan, W.; Wu, H., Stochastic modeling of the dynamics of CD4+ T-cell infection by HIV and some Monte Carlo studies, Math. Biosci., 147, 173 (1998) · Zbl 0887.92021
[32] Tan, W.; Xiang, Z., Some state space models of HIV pathogenesis under treatment by anti-viral drugs in HIV-infected individuals, Math. Biosci., 156, 69, 69 (1999) · Zbl 0947.92018
[33] Tuckwell, H. C.; Corfec, E. L., A stochastic model for early HIV-1 population dynamics, J. Theor. Biol., 195, 451 (1998)
[34] Wick, D.; Self, S. G., Early HIV infection in vivo: Branching-process model for studying timing of immune responses and drug therapy, Math. Biosci., 165, 115 (2000) · Zbl 0963.92022
[35] Wu, H.; Ding, A. A.; de Gruttola, V., Estimation of HIV dynamic parameters, Stat. Medicine, 17, 2463 (1998)
[36] Kirschner, D.; Lenhart, S.; Serbin, S., Optimal control of chemotherapy of HIV, J. Math. Biol., 35, 775 (1997) · Zbl 0876.92016
[37] Wein, L. M.; Zeinos, S. A.; Nowak, M. A., Dynamic multidrug therapies for HIV: A control theoretic approach, J. Theor. Biol., 185, 15 (1997)
[38] Gumel, A. B.; Shivakumar, P. N.; Sahai, B. M., A mathematical model for the dynamics of HIV-1 during the typical course of infection, Nonlinear Analy., 47, 1773 (2001) · Zbl 1042.92512
[39] Verotta, D.; Schaedeli, F., Non-linear dynamics models characterizing long-term virological data from AIDS clinical trials, Math. Biosci., 176, 163 (2002) · Zbl 1015.92022
[40] Nowak, M. A.; May, R. M., Virus Dynamics: Mathematical Principles of Immunology and Virology (2000), Oxford University: Oxford University New York, NY · Zbl 1101.92028
[41] Perelson, A. S., Modeling viral and immune system dynamics, Nature Rev. Immunol., 2, 28 (2002)
[42] Perelson, A. S.; Nelson, P. W., Mathematical analysis of HIV-1 dynamics in vivo, SIAM Rev., 41, 3 (1999) · Zbl 1078.92502
[43] Cox, D. R.; Miller, H. D., The Theory of Stochastic Processes (1965), Chapman and Hall: Chapman and Hall London · Zbl 0149.12902
[44] Jensen, A., An elucidation of Erlang’s statistical works through the theory of stochastic processes, (Brockmeyer, E.; Halstrøm, H. L.; Jensen, A., The Life and Works of A.K. Erlang (1948), The Copenhagen Telephone Company: The Copenhagen Telephone Company Copenhagen), 23 · Zbl 0033.05101
[45] Llyod, A. L., Destabilization of epidemic models with the inclusion of realistic distributions of infectious periods, Proc. Roy. Soc. Lond. B, 268, 985 (2001)
[46] MacDonald, N., Biological Delay Systems: Linear Stability Theory (1989), Cambridge University: Cambridge University Cambridge · Zbl 0669.92001
[47] Banks, H. T., Identification of nonlinear delay systems using spline methods, (Lakshmikantham, V., Nonlinear Phenomena in Mathematical Sciences (1982), Academic Press: Academic Press New York, NY), 47
[48] Banks, H. T.; Burns, J. A., Hereditary control problems: Numerical methods based on averaging approximations, SIAM J. Control Optim., 16, 169 (1978) · Zbl 0379.49025
[49] Banks, H. T.; Kappel, F., Spline approximations for functional differential equations, J. Diff. Eqs., 34, 496 (1979) · Zbl 0422.34074
[50] Frisch, F.; Holme, H., The characteristic solution of a mixed difference and differential equation occurring in economic dynamics, Econometrica, 3, 225 (1935) · JFM 61.1326.05
[51] Hutchinson, G. E., Circular causal systems in ecology, Ann. New York Acad. Sci., 50, 221 (1948)
[52] Minorsky, N., Self-excited oscillations in a dynamical system possessing retarded actions, J. Appl. Mech., 9, 65 (1942)
[53] May, R. M., Stability and Complexity in Model Ecosystems (2001), Princeton University: Princeton University Princeton, NJ, (orignially published 1973) · Zbl 1044.92047
[54] J.D. Murray, Mathematical Biology, Biomathematics, vol. 19, Springer, New York, NY, 1989; J.D. Murray, Mathematical Biology, Biomathematics, vol. 19, Springer, New York, NY, 1989 · Zbl 0682.92001
[55] R. Bellman, K.L. Cooke, Differential-Difference Equations, Mathematics in Science and Engineering, vol. 6, Academic Press, New York, NY, 1963; R. Bellman, K.L. Cooke, Differential-Difference Equations, Mathematics in Science and Engineering, vol. 6, Academic Press, New York, NY, 1963 · Zbl 0105.06402
[56] R.D. Driver, Ordinary and Delay Differential Equations, Applied Mathematical Sciences, vol. 20, Springer, New York, NY, 1977; R.D. Driver, Ordinary and Delay Differential Equations, Applied Mathematical Sciences, vol. 20, Springer, New York, NY, 1977 · Zbl 0374.34001
[57] J.M. Cushing, Integrodifferential Equations and Delay Models in Population Dynamics, Lecture Notes in Biomathematics, vol. 20, Springer, New York, NY, 1977; J.M. Cushing, Integrodifferential Equations and Delay Models in Population Dynamics, Lecture Notes in Biomathematics, vol. 20, Springer, New York, NY, 1977 · Zbl 0363.92014
[58] Y. Kuang, Delay Differential Equations With Applications in Population Dynamics, no. 191 in Mathematics in Science and Engineering, Academic Press, New York, NY, 1993; Y. Kuang, Delay Differential Equations With Applications in Population Dynamics, no. 191 in Mathematics in Science and Engineering, Academic Press, New York, NY, 1993 · Zbl 0777.34002
[59] O. Diekmann, S.A. van Gils, S.M.V. Lunel, H.O. Walther, Delay Equations: Functional-, Complex-, and Nonlinear Analysis, Applied Mathematical Sciences, vol. 110, Springer, New York, NY, 1995; O. Diekmann, S.A. van Gils, S.M.V. Lunel, H.O. Walther, Delay Equations: Functional-, Complex-, and Nonlinear Analysis, Applied Mathematical Sciences, vol. 110, Springer, New York, NY, 1995 · Zbl 0826.34002
[60] Górecki, H.; Fuksa, S.; Grabowski, P.; Korytowski, A., Analysis and Synthesis of Time Delay Systems (1989), John Wiley: John Wiley New York, NY · Zbl 0695.93002
[61] J.K. Hale, S.M.V. Lunel, Introduction to Functional Differential Equations, Applied Mathematical Sciences, vol. 99, Springer, New York, NY, 1993; J.K. Hale, S.M.V. Lunel, Introduction to Functional Differential Equations, Applied Mathematical Sciences, vol. 99, Springer, New York, NY, 1993 · Zbl 0787.34002
[62] D.M. Bortz, R. Guy, J. Hood, K. Kirkpatrick, V. Nguyen, V. Shimanovich, Modeling HIV infection dynamics using delay equations, Tech. Rep. CRSC-TR00-24, Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, in: P.A. Gremaud, Z. Li, R.C. Smith, H.T. Tran (Eds.), Proceedings of the 2000 Industrial Mathematics Modeling Workshop for Graduate Students, Oct. 2000; D.M. Bortz, R. Guy, J. Hood, K. Kirkpatrick, V. Nguyen, V. Shimanovich, Modeling HIV infection dynamics using delay equations, Tech. Rep. CRSC-TR00-24, Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, in: P.A. Gremaud, Z. Li, R.C. Smith, H.T. Tran (Eds.), Proceedings of the 2000 Industrial Mathematics Modeling Workshop for Graduate Students, Oct. 2000
[63] Rogel, M. E.; Wu, L. I.; Emerman, M., The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection, J. Virol., 69, 882 (1995)
[64] Hoppensteadt, F. C., Mathematical Methods of Population Biology (1982), Cambridge University: Cambridge University Cambridge · Zbl 0373.92015
[65] D.M. Bortz, Modeling, Analysis, and Estimation of an in vitro HIV Infection Using Functional Differential Equations, Ph.D. dissertation, North Carolina State University, Raleigh, NC, 2002; D.M. Bortz, Modeling, Analysis, and Estimation of an in vitro HIV Infection Using Functional Differential Equations, Ph.D. dissertation, North Carolina State University, Raleigh, NC, 2002
[66] Banks, H. T.; Fitzpatrick, B. G., Statistical methods for model comparison in parameter estimation problems for distributed systems, J. Math. Biol., 28, 501 (1990) · Zbl 0732.62061
[67] H.T. Banks, D.M. Bortz, A parameter sensitivity methodology in the context of HIV delay equation models, Tech. Rep. CRSC-TR02-24, Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, Aug. 2002; J. Math. Biol., submitted for publication; H.T. Banks, D.M. Bortz, A parameter sensitivity methodology in the context of HIV delay equation models, Tech. Rep. CRSC-TR02-24, Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC, Aug. 2002; J. Math. Biol., submitted for publication · Zbl 1083.92025
[68] Banks, H. T.; Kunisch, K., Estimation Techniques for Distributed Parameter Systems (1989), Birkhäuser: Birkhäuser Boston, MA · Zbl 0695.93020
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.