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Proc Biol Sci. Oct 22, 2001; 268(1481): 2085–2095.
PMCID: PMC1088852

The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications.


This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti-HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science. 1996 Apr 5;272(5258):54–60. [PubMed]
  • Arnaout RA, Nowak MA, Wodarz D. HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing? Proc Biol Sci. 2000 Jul 7;267(1450):1347–1354. [PMC free article] [PubMed]
  • Battegay M, Moskophidis D, Rahemtulla A, Hengartner H, Mak TW, Zinkernagel RM. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J Virol. 1994 Jul;68(7):4700–4704. [PMC free article] [PubMed]
  • Bonhoeffer S, Rembiszewski M, Ortiz GM, Nixon DF. Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection. AIDS. 2000 Oct 20;14(15):2313–2322. [PubMed]
  • Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997 May 8;387(6629):183–188. [PubMed]
  • Cooper LN. Theory of an immune system retrovirus. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9159–9163. [PMC free article] [PubMed]
  • Dalod M, Harzic M, Pellegrin I, Dumon B, Hoen B, Sereni D, Deschemin JC, Levy JP, Venet A, Gomard E. Evolution of cytotoxic T lymphocyte responses to human immunodeficiency virus type 1 in patients with symptomatic primary infection receiving antiretroviral triple therapy. J Infect Dis. 1998 Jul;178(1):61–69. [PubMed]
  • Dalod M, Dupuis M, Deschemin JC, Sicard D, Salmon D, Delfraissy JF, Venet A, Sinet M, Guillet JG. Broad, intense anti-human immunodeficiency virus (HIV) ex vivo CD8(+) responses in HIV type 1-infected patients: comparison with anti-Epstein-Barr virus responses and changes during antiretroviral therapy. J Virol. 1999 Sep;73(9):7108–7116. [PMC free article] [PubMed]
  • de Wolf F, Spijkerman I, Schellekens PT, Langendam M, Kuiken C, Bakker M, Roos M, Coutinho R, Miedema F, Goudsmit J. AIDS prognosis based on HIV-1 RNA, CD4+ T-cell count and function: markers with reciprocal predictive value over time after seroconversion. AIDS. 1997 Dec;11(15):1799–1806. [PubMed]
  • Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998 Dec 17;396(6712):690–695. [PubMed]
  • Essunger P, Perelson AS. Modeling HIV infection of CD4+ T-cell subpopulations. J Theor Biol. 1994 Oct 21;170(4):367–391. [PubMed]
  • Fahey JL, Taylor JM, Manna B, Nishanian P, Aziz N, Giorgi JV, Detels R. Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements. AIDS. 1998 Sep 10;12(13):1581–1590. [PubMed]
  • Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996 Apr 1;124(7):654–663. [PubMed]
  • Ferguson NM, deWolf F, Ghani AC, Fraser C, Donnelly CA, Reiss P, Lange JM, Danner SA, Garnett GP, Goudsmit J, et al. Antigen-driven CD4+ T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15167–15172. [PMC free article] [PubMed]
  • Finzi D, Siliciano RF. Viral dynamics in HIV-1 infection. Cell. 1998 May 29;93(5):665–671. [PubMed]
  • Fleury S, de Boer RJ, Rizzardi GP, Wolthers KC, Otto SA, Welbon CC, Graziosi C, Knabenhans C, Soudeyns H, Bart PA, et al. Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy. Nat Med. 1998 Jul;4(7):794–801. [PubMed]
  • Fraser C, Ferguson NM, Ghani AC, Prins JM, Lange JM, Goudsmit J, Anderson RM, de Wolf F. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS. 2000 Apr 14;14(6):659–669. [PubMed]
  • Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, Shih R, Lewis J, Wiley DJ, Phair JP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999 Apr;179(4):859–870. [PubMed]
  • Grossman Z, Feinberg MB, Paul WE. Multiple modes of cellular activation and virus transmission in HIV infection: a role for chronically and latently infected cells in sustaining viral replication. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6314–6319. [PMC free article] [PubMed]
  • Haase AT. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol. 1999;17:625–656. [PubMed]
  • Harrer T, Harrer E, Kalams SA, Elbeik T, Staprans SI, Feinberg MB, Cao Y, Ho DD, Yilma T, Caliendo AM, et al. Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection. AIDS Res Hum Retroviruses. 1996 May 1;12(7):585–592. [PubMed]
  • Hazenberg MD, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC, Boucher CA, Coutinho RA, Lange JM, Rinke de Wit TF, Tsegaye A, et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med. 2000 Sep;6(9):1036–1042. [PubMed]
  • Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, Miedema F, Hamann D. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000 Jan 1;95(1):249–255. [PubMed]
  • Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, Schmidt D, Hoh R, Neese R, Macallan D, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med. 1999 Jan;5(1):83–89. [PubMed]
  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. [PubMed]
  • Jurriaans S, Van Gemen B, Weverling GJ, Van Strijp D, Nara P, Coutinho R, Koot M, Schuitemaker H, Goudsmit J. The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course? Virology. 1994 Oct;204(1):223–233. [PubMed]
  • Kalams SA, Buchbinder SP, Rosenberg ES, Billingsley JM, Colbert DS, Jones NG, Shea AK, Trocha AK, Walker BD. Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol. 1999 Aug;73(8):6715–6720. [PMC free article] [PubMed]
  • Kalams SA, Goulder PJ, Shea AK, Jones NG, Trocha AK, Ogg GS, Walker BD. Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol. 1999 Aug;73(8):6721–6728. [PMC free article] [PubMed]
  • Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet. 1998 Mar 7;351(9104):723–724. [PubMed]
  • Kaufmann GR, Cunningham P, Kelleher AD, Zaunders J, Carr A, Vizzard J, Law M, Cooper DA. Patterns of viral dynamics during primary human immunodeficiency virus type 1 infection. The Sydney Primary HIV Infection Study Group. J Infect Dis. 1998 Dec;178(6):1812–1815. [PubMed]
  • Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, Vernazza P, Sudre P, Flepp M, Furrer H, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet. 1999 Mar 13;353(9156):863–868. [PubMed]
  • Lepri AC, Sabin CA, Pezzotti P, England PD, Phillips AN, Rezza G. Is there a general tendency for CD4 lymphocyte decline to speed up during human immunodeficiency virus infection? Evidence from the Italian Seroconversion Study. J Infect Dis. 1997 Apr;175(4):775–780. [PubMed]
  • Little SJ, McLean AR, Spina CA, Richman DD, Havlir DV. Viral dynamics of acute HIV-1 infection. J Exp Med. 1999 Sep 20;190(6):841–850. [PMC free article] [PubMed]
  • Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Oct 1;16(2):83–92. [PubMed]
  • Lyles CM, Dorrucci M, Vlahov D, Pezzotti P, Angarano G, Sinicco A, Alberici F, Alcorn TM, Vella S, Rezza G. Longitudinal human immunodeficiency virus type 1 load in the italian seroconversion study: correlates and temporal trends of virus load. J Infect Dis. 1999 Oct;180(4):1018–1024. [PubMed]
  • McLean AR, Nowak MA. Models of interactions between HIV and other pathogens. J Theor Biol. 1992 Mar 7;155(1):69–86. [PubMed]
  • McMichael AJ, Ogg G, Wilson J, Callan M, Hambleton S, Appay V, Kelleher T, Rowland-Jones S. Memory CD8+ T cells in HIV infection. Philos Trans R Soc Lond B Biol Sci. 2000 Mar 29;355(1395):363–367. [PMC free article] [PubMed]
  • Margolick JB, Donnenberg AD, Muñoz A, Park LP, Bauer KD, Giorgi JV, Ferbas J, Saah AJ. Changes in T and non-T lymphocyte subsets following seroconversion to HIV-1: stable CD3+ and declining CD3- populations suggest regulatory responses linked to loss of CD4 lymphocytes. The Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1993 Feb;6(2):153–161. [PubMed]
  • Margolick JB, Muñoz A, Donnenberg AD, Park LP, Galai N, Giorgi JV, O'Gorman MR, Ferbas J. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study. Nat Med. 1995 Jul;1(7):674–680. [PubMed]
  • Matloubian M, Concepcion RJ, Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol. 1994 Dec;68(12):8056–8063. [PMC free article] [PubMed]
  • Mellors JW, Rinaldo CR, Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167–1170. [PubMed]
  • Mittler JE, Levin BR, Antia R. T-cell homeostasis, competition, and drift: AIDS as HIV-accelerated senescence of the immune repertoire. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Jul;12(3):233–248. [PubMed]
  • Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d'Arminio Monforte A, Yust I, Bruun JN, Phillips AN, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet. 1998 Nov 28;352(9142):1725–1730. [PubMed]
  • Moriuchi H, Moriuchi M, Mizell SB, Ehler LA, Fauci AS. In vitro reactivation of human immunodeficiency virus 1 from latently infected, resting CD4+ T cells after bacterial stimulation. J Infect Dis. 2000 Jun;181(6):2041–2044. [PubMed]
  • Nowak MA, Anderson RM, McLean AR, Wolfs TF, Goudsmit J, May RM. Antigenic diversity thresholds and the development of AIDS. Science. 1991 Nov 15;254(5034):963–969. [PubMed]
  • Nowak MA, May RM, Phillips RE, Rowland-Jones S, Lalloo DG, McAdam S, Klenerman P, Köppe B, Sigmund K, Bangham CR, et al. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature. 1995 Jun 15;375(6532):606–611. [PubMed]
  • Nowak MA, Lloyd AL, Vasquez GM, Wiltrout TA, Wahl LM, Bischofberger N, Williams J, Kinter A, Fauci AS, Hirsch VM, et al. Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection. J Virol. 1997 Oct;71(10):7518–7525. [PMC free article] [PubMed]
  • Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, Segal JP, Cao Y, Rowland-Jones SL, Cerundolo V, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science. 1998 Mar 27;279(5359):2103–2106. [PubMed]
  • Ogg GS, Jin X, Bonhoeffer S, Moss P, Nowak MA, Monard S, Segal JP, Cao Y, Rowland-Jones SL, Hurley A, et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol. 1999 Jan;73(1):797–800. [PMC free article] [PubMed]
  • Orendi JM, Bloem AC, Borleffs JC, Wijnholds FJ, de Vos NM, Nottet HS, Visser MR, Snippe H, Verhoef J, Boucher CA. Activation and cell cycle antigens in CD4+ and CD8+ T cells correlate with plasma human immunodeficiency virus (HIV-1) RNA level in HIV-1 infection. J Infect Dis. 1998 Nov;178(5):1279–1287. [PubMed]
  • Ostrowski MA, Krakauer DC, Li Y, Justement SJ, Learn G, Ehler LA, Stanley SK, Nowak M, Fauci AS. Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies. J Virol. 1998 Oct;72(10):7772–7784. [PMC free article] [PubMed]
  • Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens PT. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med. 1998 Feb;4(2):208–214. [PubMed]
  • Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853–860. [PubMed]
  • Parren PW, Moore JP, Burton DR, Sattentau QJ. The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity. AIDS. 1999;13 (Suppl A):S137–S162. [PubMed]
  • Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. [PubMed]
  • Phillips AN. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science. 1996 Jan 26;271(5248):497–499. [PubMed]
  • Phillips AN, Lee CA, Elford J, Janossy G, Timms A, Bofill M, Kernoff PB. Serial CD4 lymphocyte counts and development of AIDS. Lancet. 1991 Feb 16;337(8738):389–392. [PubMed]
  • Phillips AN, Sabin CA, Elford J, Bofill M, Timms A, Janossy G, Lee CA. Serum beta 2-microglobulin at HIV-1 seroconversion as a predictor of severe immunodeficiency during 10 years of followup. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Nov 1;13(3):262–266. [PubMed]
  • Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med. 1999 May;5(5):518–525. [PubMed]
  • Powderly WG. The interaction of opportunistic infections and HIV replication. AIDS. 1999 Sep 10;13(13):1603–1606. [PubMed]
  • Putter H, Prins JM, Jurriaans S, Roos M, Ferguson NM, van Praag R, van der Hoek L, Schuitemaker H, Anderson RM, Goudsmit J, et al. Slower decline of plasma HIV-1 RNA following highly suppressive antiretroviral therapy in primary compared with chronic infection. AIDS. 2000 Dec 22;14(18):2831–2839. [PubMed]
  • Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, Macken CA, Perelson AS, Markowitz M, Ho DD. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med. 2000 Jan;6(1):82–85. [PubMed]
  • Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D'Aquila RT, Goulder PJ, Walker BD. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000 Sep 28;407(6803):523–526. [PubMed]
  • Stafford MA, Corey L, Cao Y, Daar ES, Ho DD, Perelson AS. Modeling plasma virus concentration during primary HIV infection. J Theor Biol. 2000 Apr 7;203(3):285–301. [PubMed]
  • Staprans SI, Hamilton BL, Follansbee SE, Elbeik T, Barbosa P, Grant RM, Feinberg MB. Activation of virus replication after vaccination of HIV-1-infected individuals. J Exp Med. 1995 Dec 1;182(6):1727–1737. [PMC free article] [PubMed]
  • Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. [PMC free article] [PubMed]
  • Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. [PubMed]
  • Wodarz D, Lloyd AL, Jansen VA, Nowak MA. Dynamics of macrophage and T cell infection by HIV. J Theor Biol. 1999 Jan 7;196(1):101–113. [PubMed]
  • Wodarz D, Arnaout RA, Nowak MA, Lifson JD. Transient antiretroviral treatment during acute simian immunodeficiency virus infection facilitates long-term control of the virus. Philos Trans R Soc Lond B Biol Sci. 2000 Aug 29;355(1400):1021–1029. [PMC free article] [PubMed]
  • Wodarz D, May RM, Nowak MA. The role of antigen-independent persistence of memory cytotoxic T lymphocytes. Int Immunol. 2000 Apr;12(4):467–477. [PubMed]
  • Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. [PubMed]

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