Generals die in friendly fire, or modeling immune response to HIV. (English) Zbl 1072.92028

Summary: We develop a kinetic model for CD8 T lymphocytes (CTL) whose purpose is to kill cells infected with viruses and intracellular parasites. Using a set of first-order nonlinear differential equations, the model predicts how numbers of different cell types involved in CTL response depend on time. The model postulates that CTL response requires continuous presence of professional antigen-presenting cells (APC) comprised of macrophages and dendritic cells. It assumes that any virus present in excess of a threshold level activates APC that, in turn, activate CTL that expand in number and become armed “effector” cells. In the end, APC are deactivated after the virus is cleared. The lack of signal from APC causes effector cells to differentiate, by default, into “transitory cells” that either die, or, in a small part, become long-lived memory cells. Viruses capable of infecting APC will cause premature retirement of effector CTL. If transitory cells encounter a virus, which takes place after the premature depletion, CTL become anergic (unresponsive to external stimuli).
The model is designed to fit recent experiments on primary CTL response to simian immunodeficiency virus closely related to HIV and lymphocytic choriomeningitis virus. The two viruses are known to infect APC and make them targets for CTL they are supposed to control. Both viruses cause premature depletion and anergy of CTL and persist in the host for life.


92C50 Medical applications (general)
Full Text: DOI


[1] Altman, J.D.; Moss, P.A.H.; Goulder, P.J.R.; Barouch, D.H.; McHeyzer-Williams, M.G.; Bell, J.I.; McMichael, A.J.; Davis, M.M., Phenotypic analysis of antigen-specific T lymphocytes, Science, 274, 94-96, (1996)
[2] Bocharov, G.A., Modelling the dynamics of LCMV infection in miceconventional and exhaustive CTL responses, J. theor. biol., 192, 283-308, (1998)
[3] Burnham, K.; Anderson, D., Model selection and inference. A practical information-theoretic approach, (1998), Springer New York · Zbl 0920.62006
[4] Christensen, J.P.; Marker, O.; Thomsen, A.R., The role of CD4+ T cells in cell-mediated immunity to lcmvstudies in MHC class I and class II deficient mice, Scand. J. immunol., 40, 373-382, (1994)
[5] De Boer, R.J.; Homann, D.; Perelson, A.S., Different dynamics of CD4 and CD8 T cell responses during and after acute lymphocytic choriomeningitis virus infection, J. immunol., 171, 3928-3935, (2003)
[6] De Boer, R.J.; Oprea, M.; Antia, R.; Murali-Krishna, K.; Ahmed, R.; Perelson, A.S., Recruitment times, proliferation, and apoptosis rates during the CD8 T-cell response to lymphocytic choriomeningitis virus, J. virol., 75, 10663-10669, (2001)
[7] Grossman, Z.; Herberman, R.B.; Dimitrov, D.S., T cell turnover in SIV infection, Science, 284, 555a-555b, (1999)
[8] Janssen, E.M.; Lemmens, E.E.; Wolfe, T.; Christen, U.; von Herrath, M.G.; Schoenberger, S.P., CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes, Nature, 421, 852-856, (2003)
[9] Kalams, S.A.; Walker, B.D., The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses [comment], J. exp. med., 188, 2199-2204, (1998)
[10] Kuroda, M.J.; Schmitz, J.E.; Charini, W.A.; Nickerson, C.E.; Lifton, M.A.; Lord, C.I.; Forman, M.A.; Letvin, N.L., Emergence of CTL coincides with clearance of virus during primary Simian immunodeficiency virus infection in rhesus monkeys, J. immunol., 162, 5127-5133, (1999)
[11] Matloubian, M.; Concepcion, R.J.; Ahmed, R., CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection, J. virol., 68, 8056-8063, (1994)
[12] Mohri, H.; Bonhoeffer, S.; Monard, S.; Perelson, A.S.; Ho, D.D., Rapid turnover of T lymphocytes in SIV-infected rhesus macaques, Science, 279, 1223-1227, (1998)
[13] Moskophidis, D.; Lechner, F.; Pircher, H.; Zinkernagel, R.M., Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells, Nature, 362, 758-761, (1993)
[14] Murali-Krishna, K.; Altman, J.D.; Suresh, M.; Sourdive, D.J.; Zajac, A.J.; Miller, J.D.; Slansky, J.; Ahmed, R., Counting antigen-specific CD8 T cellsa reevaluation of bystander activation during viral infection, Immunity, 8, 177-187, (1998)
[15] Ogg, G.S.; Jin, X.; Bonhoeffer, S.; Moss, P.; Nowak, M.A.; Monard, S.; Segal, J.P.; Cao, Y.; Rowland-Jones, S.L.; Hurley, A.; Markowitz, M.; Ho, D.D.; McMichael, A.J.; Nixon, D.F., Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy, J. virol., 73, 797-800, (1999)
[16] Ou, R.; Zhou, S.; Huang, L.; Moskophidis, D., Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells, J. virol., 75, 8407-8423, (2001)
[17] Rouzine, I.; McKenzie, F.E., Link between immune response and parasite synchronization in malaria, Proc. natl. acad. sci. USA, 100, 3473-3478, (2003)
[18] Rouzine, I.M.; Coffin, J.M., Interplay between experiment and theory in development of a working model for HIV-1 population dynamics, (), 225-262
[19] Rouzine, I.M.; Coffin, J.M., T cell turnover in SIV infection, Science, 284, 555b, (1999)
[20] Wodarz, D.; Klenerman, P.; Nowak, M.A., Dynamics of cytotoxic T-lymphocyte exhaustion, Proc. R. soc. lond. B. biol. sci., 265, 191-203, (1998)
[21] Zajac, A.J.; Blattman, J.N.; Murali-Krishna, K.; Sourdive, D.J.; Suresh, M.; Altman, J.D.; Ahmed, R., Viral immune evasion due to persistence of activated T cells without effector function, J. exp. med., 188, 2205-2213, (1998)
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