Skip to main content

Advertisement

SpringerLink
Log in

Predicting differential responses to structured treatment interruptions during HAART

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Highly active antiretroviral therapy (HAART) has been used clinically in various administration schemes for several years. However, due to the development of drug resistance, evolution of viral strains, serious side effects, and poor patient compliance, the combination of drugs used in HAART fails to effectively contain virus long term in a high proportion of patients. Our group and others have suggested a change to the usual regimen of continuous HAART through structured treatment interruptions (STIs). STIs may provide similar clinical benefits as continuous treatment such as reduced viral loads and reestablishment of CD4+ T cells while allowing patients drug holidays. We explore the use of STIs using a previously published model that accurately represents CD4+ T-cell counts and viral loads during both untreated HIV-1 infection and HAART therapy. We simulate the effects of different STI regimens including weekly and monthly interruptions together with variations in treatment initiation time. We predict that differential responses to STIs as observed in conflicting clinical trial data are impacted by the duration of the interruption, stage of infection at initiation of treatment, strength of the immune system in suppressing virus, or pre-therapy CD4+ T-cell count or virus load. Our results indicate that dynamics occurring below the limit of detection (LOD) are influenced by these factors, and contribute to reemergence or suppression of virus during interruptions. Simulations predict that short-term viral suppression with varying interruptions strategies does not guarantee long-term clinical benefit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbas, U. and J. Mellors (2002). Interruption of antiretroviral therapy to augment immune control of chronic HIV-1 infection: rish without reward. Proc. Natl. Acad. Sci. 99, 13377–13378.

    Google Scholar 

  • Altfeld, M., J. van Lunzen, N. Frahm, X. Yu, C. Schneider, R. Eldridge, M. Feeney, D. Meyer-Olson, H.-J. Stellbrink and B. Walker (2002). Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection. J. Clin. Invest. 109, 837–843.

    Article  Google Scholar 

  • Altfeld, M. and B. Walker (2001). Less is more? STI in acute and chronic HIV-1 infection. Nat. Med. 7, 881–884.

    Article  Google Scholar 

  • Ammassari, A. et al. (2001). Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J. Acquir. Immune Defic. Syndr. 28, 445–449.

    Google Scholar 

  • Ananworanich, J. et al. (2003). Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial. AIDS 17, F33–F37.

    Article  Google Scholar 

  • Bajaria, S., G. Webb, M. Cloyd and D. Kirschner (2002). Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression. J. Acquir. Immune Defic. Syndr. 30, 41–58.

    Article  Google Scholar 

  • Bangsberg, D. et al. (2003). High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 17, 1925–1932.

    Article  Google Scholar 

  • Bartlett, J. (2002). Addressing the challenges of adherence. J. Acquir. Immune Defic. Syndr. 29, S2–S10.

    Google Scholar 

  • Blankson, J., D. Finzi, T. Pierson, B. Sabundayo, K. Chadwick, J. Margolick, T. Quinn and R. Siliciano (2000). Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. J. Infect. Dis. 182, 1636–1642.

    Article  Google Scholar 

  • Blankson, J., J. Gallant, T. Quinn, J. Bartlett and R. Siliciano (2002a). Loss of HIV-1 specific immunity during treatment interruption in 2 chronically infected patients. JAMA 288, 162–164.

    Article  Google Scholar 

  • Blankson, J., J. Siliciano, D. Finzi, T. Quinn, J. Gallant and R. Siliciano (2002b). Rapid initial decay of latently infected cells following the re-initiation of HAART in chronically HIV-1 infected patients with treatment interruptions. Abstracts from the 9th Conference on Retroviruses and Opportunistic Infections, Abstract 491-M.

  • Bonhoeffer, S., M. Rembiszewski, G. Ortiz and D. Nixon (2000). Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection. AIDS 14, 2313–2322.

    Article  Google Scholar 

  • Carcelain, G., R. Tubiana, A. Samri, V. Calvez, C. Delaugerre, H. Agut, C. Katlama and B. Autran (2001). Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection. J. Virol. 75, 234–241.

    Article  Google Scholar 

  • Cavert, W. et al. (1997). Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960–964.

    Article  Google Scholar 

  • Chen, J. and M. Cloyd (1999). The potential importance of HIV-induction of lymphocyte homing to lymph nodes. Int. Immunol. 11, 1591–1594.

    Article  Google Scholar 

  • Chun, T. et al. (1997a). Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188.

    Article  Google Scholar 

  • Chun, T., L. Stuyver, S. Mizell, L. Ehler, J. Mican, M. Baseler, A. Lloyd, M. Nowak and A. Fauci (1997b). Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. 94, 13193–13197.

  • Chun, T.-W., R. Davey and D. Engel (1999). Re-emergence of HIV after stopping therapy. Nature 401, 874–875.

    Article  Google Scholar 

  • Cloyd, M., J. Chen and L. Wang (2000). How does HIV cause AIDS? The homing theory. Mol. Med. Today 6, 108–111.

    Article  Google Scholar 

  • Cohen Stuart, J., A. Wensing, C. Kovacs, M. Righart, D. de Jong, S. Kaye, R. Schuurman, C. Visser and C. Boucher (2001). Transient relapses (’blips’) of plasma HIV RNA levels during HAART are associated with drug resistance. J. Acquir. Immune Defic. Syndr. 28, 105–113.

    Article  Google Scholar 

  • Crowe, S. and S. Sonza (2000). HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. J. Leukoc. Biol. 68, 345–350.

    Google Scholar 

  • Davey, R. et al. (1999). A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. Proc. Natl. Acad. Sci. 96, 15109-15114.

    Google Scholar 

  • Deeks, S. (2001). Durable HIV treatment benefit despite low-level viremia. JAMA 286, 224–226.

    Article  Google Scholar 

  • Devereux, H., A. Burke, C. Lee and M. Johnson (2002). In vivo HIV-1 compartmentalization: drug resistance-associated mutation distribution. J. Med. Virol. 66, 8–12.

    Article  Google Scholar 

  • Dorman, K., A. Kaplan, K. Lange and J. Sinsheimer (2000). Mutation takes no vacation: can structured treatment interruptions increase the risk of drug-resistant HIV-1? J. Acquir. Immune Defic. Syndr. 25, 398–402.

    Article  Google Scholar 

  • Dybul, M. et al. (2001). Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Proc. Natl. Acad. Sci. 98, 15161–15166.

    Google Scholar 

  • Dybul, M. et al. (2003). A randomized, controlled trial of long cycle structured intermittent versus continuous ARV therapy for chronic HIV infection. Abstracts from the 10th Conference on Retroviruses and Opportunistic Infections, Abstract 681b.

  • Fagard, C. et al. (2003). A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch. Intern. Med. 163, 1220–1226.

    Article  Google Scholar 

  • Fauci, A., G. Pantaleo, S. Stanley and D. Weissman (1996). Immunipathogenic mechanisms of HIV infection. Ann. Intern. Med. 124, 654–663.

    Google Scholar 

  • Fellay, J., K. Boubaker and B. Ledergerber (2001). Prevalence of adverse effects associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 358, 1322–1327.

    Article  Google Scholar 

  • Finzi, D. et al. (1999). Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 5, 512–517.

    Article  Google Scholar 

  • Fisher, M., R. Hafner, C. Schenider, A. Trkola, B. Joos, H. Joller, B. Hisrchel, R. Weber and H. Gunthard (2003). HIV RNA in plasma rebounds within days during structured treatment interruptions. AIDS 17, 195–199.

    Article  Google Scholar 

  • Frost, S., J. Martinez-Picado, L. Ruiz, B. Clotet and A. Brown (2002). Viral dynamics during structured treatment interruptions of chronic human immunodeficiency virus type 1 infection. J Virol 76, 968–979.

    Google Scholar 

  • Furtado, M., D. Callaway, J. Phair, K. Kunstman, J. Stanton, C. Macken, A. Perelson and S. Wolinsky (1999). Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N. Engl. J. Med. 340, 1614–1622.

    Article  Google Scholar 

  • Garcia, F. et al. (2001). The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS 15, F29–F40.

    Article  Google Scholar 

  • Garcia, F., M. Plana, M. Arnedo, G. Ortiz, J. Miro, L. Lopalco, F. Lori, T. Pumarola, T. Gallart and J. Gatell (2003). A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. AIDS 17, 43–51.

    Article  Google Scholar 

  • Greenough, T., D. Brettler, F. Kirchhoff, L. Alexander, R. Desrosiers, S. O’Brien, M. Somesundaran, K. Luzuriaga and J. Sullivan (1999). Long-term non-progressive infection with human immunodeficiency virus type 1 in a hemophilia cohort. J. Infect. Dis. 180, 1790–1802.

    Article  Google Scholar 

  • Gulick, R. (2002). Structured treatment interruption in patients infected with HIV. Drugs 62, 245–253.

    Article  Google Scholar 

  • Haase, A. (1999). Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17, 625–656.

    Article  Google Scholar 

  • Hance, A., V. Lemiale, J. Izopet, D. Lecossier, V. Joly, P. Massip, F. Mammano, D. Descamps, F. Brun-Vezinet and F. Clavel (2001). Changes in human immunodeficiency virus type 1 populations after treatment interruption in patients failing antiretroviral therapy. J. Virol. 75, 6410–6417.

    Article  Google Scholar 

  • Harder, B. (2003). Zealous adherence: erratic HIV therapy hasn’t fueled resistance. Sci. News 164, 149–150.

    Google Scholar 

  • Harrington, M. and C. Carpenter (2000). Hit HIV-1 hard, but only when necessary. Lancet 355, 2147–2152.

    Article  Google Scholar 

  • Haslett, P., D. Nixon, Z. Shen, M. Larsson, W. Cox, R. Manandhar, S. Donahoe and G. Kaplan (2000). Strong human immunodeficiency virus (HIV)-specific CD4+ T cell responses in a cohort of chronically infected patients are associated with interruptions in anti-HIV chemotherapy. J. Infect. Dis. 181, 1264–1272.

    Article  Google Scholar 

  • Hatano, H., S. Vogel, C. Yoder, J. Metcalf, R. Dewar, R. Davey and M. Polis (2000). Pre-HAART HIV burden approximates post-HAART viral levels following interruption of therapy in patients with sustained viral suppression. AIDS 14, 1357–1363.

    Article  Google Scholar 

  • Havlir, D. (2002). Structured intermittent treatment for HIV disease: necessary concession or premature compromise? Proc. Natl. Acad. Sci. 99, 4–6.

    Article  Google Scholar 

  • Havlir, D. et al. (2001). Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA 286, 171–179.

    Article  Google Scholar 

  • Hengge, U., C. Borchard, S. Esser, M. Schroder, A. Mirmohammadsadegh and M. Goos (2002). Lymphocytes proliferate in blood and lymph nodes following interleukin-2 therapy in addition to highly active antiretroviral therapy. AIDS 16, 151–160.

    Article  Google Scholar 

  • Hermankova, M., S. Ray, C. Ruff, M. Powell-David, R. Ingersoll, R. D’Aquila, T. Quinn, J. Siliciano, R. Siliciano and D. Persaud (2001). HIV-1 drug resistance profiles in children and adults with viral load of 50 copies/ml receiving combination therapy. JAMA 286, 196–207.

    Article  Google Scholar 

  • Hlavacek, W., C. Wofsy and A. Perelson (1999). Dissociation of HIV-1 from follicular dendritic cells during HAART: mathematical analysis. Proc. Natl. Acad. Sci. 96, 14681–14686.

    Google Scholar 

  • Katlama, C., S. Dominguez, C. Duvivier, C. Delaugerre, G. Peytavin, M. Legrand, V. Calvez, K. Gourlain and D. Costagliola (2003). Long-term benefit of treatment interruption in salvage therapy. Abstracts from the 10th Conference on Retroviruses and Opportunistic Infections, Abstract 68.

  • Kilby, J., P. Goepfert, A. Miller, J. J. Gnann, M. Sillers, M. Saag and R. Bucy (2000). Recurrence of the acute HIV syndrome after interruption of antiretroviral therapy in a patient with chronic HIV infection: a case report. Ann. Intern. Med. 133, 435–438.

    Google Scholar 

  • Kimura, T., K. Yoshimura, K. Nishihara, Y. Maeda, S. Matsumi, A. Koito and S. Matsushita (2002). Reconstitution of spontaneous neutralizing antibody response against autologous human immunodeficiency virus during highly active antiretroviral therapy. J. Infect. Dis. 185, 53–60.

    Article  Google Scholar 

  • Kirschner, D. and G. Webb (1996). A model for treatment strategy in the chemotherapy of AIDS. Bull. Math. Biol. 58, 367–390.

    Article  MATH  Google Scholar 

  • Kirschner, D. and G. Webb (1998). Immunotherapy of HIV-1 infection. J. Biol. Syst. 6, 71–83.

    Article  MATH  Google Scholar 

  • Kirschner, D., G. Webb and M. Cloyd (2000). Model of HIV-1 disease progression based on virus-induced lymph node homing and homing-induced apoptosis of CD4+ lymphocytes. J. Acquir. Immune Defic. Syndr. 24, 352–362.

    Google Scholar 

  • Li, X., B. Moore and M. Cloyd (1996). Gradual shutdown of virus production resulting in latency is the norm during the chronic phase of human immunodeficiency virus replication and differential rates and mechanisms of shutdown are determined by viral sequences. Virology 225, 196–212.

    Article  Google Scholar 

  • Lillo, F., D. Ciuffreda, F. Veglia, B. Capiluppi, E. Mastrorilli, B. Vergani, G. Tambussi and A. Lazzarin (1999). Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection. AIDS 13, 791–796.

    Article  Google Scholar 

  • Lori, F. and J. Lisziewicz (2001). Structured treatment interruptions for the management of HIV infection. JAMA 286, 2981–2987.

    Article  Google Scholar 

  • Lori, F., R. Maserati, A. Foli, E. Seminari, J. Timpone and J. Lisziewicz (2000). Structured treatment interruptions to control HIV-1 infection. Lancet 355, 287–288.

    Article  Google Scholar 

  • Martinez-Picado, J., K. Morales-Lopetegi, T. Wrin, J. Prado, S. Frost, C. Petropoulos, B. Clotet and L. Ruiz (2002). Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions. AIDS 16, 895–899.

    Article  Google Scholar 

  • Muro-Cacho, C., G. Pantaleo and A. Fauci (1995). Analysis of apoptosis in lymph nodes of HIV-infected persons, intensity of apoptosis correlateswith the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J. Immunol. 154, 5555–5566.

    Google Scholar 

  • Neumann, A., R. Tubiana, V. Calvez, C. Robert, T.-S. Li, H. Agut, B. Autran, C. Katlama and The Comet Study Group (1999). HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. AIDS 13, 677–683.

    Article  Google Scholar 

  • Notermans, D. et al. (1999). Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type-1-infected adults. J. Infect. Dis. 180, 1050–1056.

    Article  Google Scholar 

  • Orenstein, J. et al. (2000). Rapid activation of lymph nodes and mononuclear cell HIV expression upon interrupting highly active antiretroviral therapy in patients after prolonged viral suppression. AIDS 14, 1709–1715.

    Article  Google Scholar 

  • Ortiz, G. et al. (2002). Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type-1-specific CD8+ T-cell responses in subjects treated early after infection. J. Virol. 76, 411–415.

    Article  Google Scholar 

  • Ortiz, G. et al. (1999). HIV-1 specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J. Clin. Invest. 104, R13–R18.

    Google Scholar 

  • Ortiz, G. et al. (2001). Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Proc. Natl. Acad. Sci. 98, 13288–13293.

    Google Scholar 

  • Oxenius, A., D. Price, P. Easterbrook, C. O’Callaghan, A. Kelleher, J. Whelan, G. Sontag, A. Sewell and R. Phillips (2000). Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl. Acad. Sci. 97, 3382–3387.

    Article  Google Scholar 

  • Oxenius, A. et al. (2002). Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc. Natl. Acad. Sci. 99, 13747–13752.

    Google Scholar 

  • Pakker, N., D. Notermans, R. de Boer, M. Roos, F. de Wolf, A. Hill, J. Leonard, S. Danner, F. Miedema and P. Schellekens (1998). Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proleferation. Nat. Med. 4, 208–214.

    Article  Google Scholar 

  • Pantaleo, G., S. Menzo, M. Vaccarezza, C. Graziosi, O. Cohen, J. Demarest, D. Monteofiori, J. Orenstein, C. Fox and L. Schrager (1995). Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N. Engl. J. Med. 332, 209–216.

    Article  Google Scholar 

  • Papasavvas, E., R. Grant, J. Sun, A. Mackiewicz, M. Pistilli, C. Gallo, J. Kostman, K. Mounzer, J. Shull and L. Montaner (2003). Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients. AIDS 17, 2337–2343.

    Article  Google Scholar 

  • Papasavvas, E. et al. (2000). Enhancement of human immunodeficiency virus type 1-specific CD4 T cell responses in chronically infected persons after temporary treatment interruption. J. Infect. Dis. 182, 766–775.

    Article  Google Scholar 

  • Paterson, D., S. Swindells, J. Mohr, M. Brester, E. Vergis, C. Squier, M. Wagener and N. Singh (2001). Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann. Intern. Med. 133, 21–30.

    Google Scholar 

  • Perelson, A., D. Kirschner and R. De Boer (1993). Dynamics of HIV infection of CD4+ T cells. Math. Biosci. 114, 81–125.

    Article  MATH  Google Scholar 

  • Pomerantz, R. (2002). Reservoirs of human immunodeficiency virus type 1: the main obstacles to viral eradication. Clin. Infect. Dis. 34, 91–97.

    Article  Google Scholar 

  • Poulton, M., C. Sabin and M. Fischer (2003). Immunological changes during treatment interruptions: risk factors and clinical sequelae. AIDS 17, 126–128.

    Article  Google Scholar 

  • Powderly, W. (2002). Long-term exposure to lifelong therapies. J. Acquir. Immune Defic. Syndr. 29, S28–S40.

    Google Scholar 

  • Richman, D. (2000). Normal physiology and HIV pathophysiology of human T-cell dynamics. J. Clin. Invest. 105, 565–566.

    Article  Google Scholar 

  • Rosenberg, E., M. Altfeld, S. Poon, M. Phillips, B. Wilkes, R. Eldridge, G. Robbins, R. D’Aquila, P. Goulder and B. Walker (2000). Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526.

    Article  Google Scholar 

  • Rosenberg, E., J. Billingsley, A. Caliendo, S. Boswell, P. Sax, S. Kalams and B. Walker (1997). Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450.

    Article  Google Scholar 

  • Rosenberg, Y. and G. Janossy (1999). The importance of lymphocyte trafficking in regulating blood lymphocyte levels during HIV and SIV infections. Semin. Immunol. 11, 139–154.

    Article  Google Scholar 

  • Ruiz, L. et al. (2001). HIV dynamics and T-cell immunity after three structured treatment interruption in chronic HIV-1 infection. AIDS 15, F19–F27.

    Article  Google Scholar 

  • Ruiz, L., J. Martinez-Picado, J. Romeu, R. Paredes, M. Zayat, S. Marfil, E. Negredo, G. Sirera, C. Tural and B. Clotet (2000). Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. AIDS 14, 397–403.

    Article  Google Scholar 

  • Saag, M. and J. Kilby (1999). HIV-1 and HAART: a time to cure, a time to kill. Nat. Med. 5, 609–611.

    Article  Google Scholar 

  • Sabin, C., H. Devereuz, A. Phillips, A. Hill, G. Janossy, C. Lee and C. Loveday (2000). Course of viral load throughout HIV-1 infection. J. Acquir. Immune Defic. Syndr. 23, 172–177.

    Google Scholar 

  • Schrager, L. and A. Fauci (1995). Trapped but still dangerous. Nature 377, 680–681.

    Article  Google Scholar 

  • Schweighardt, B., G. Ortiz, R. Grant, M. Wellons, G. Miralles, L. Kostrikis, J. Bartlett and D. Nixon (2002). Emergence of drug-resistant HIV-1 variants in patients undergoing structured treatment interruptions. AIDS 16, 2342–2344.

    Article  Google Scholar 

  • Sprent, J. (1973). Circulating T and B lymphocytes of the mouse, I. Migratory properties. Cell. Immunol. 7, 40–59.

    Article  Google Scholar 

  • Sprent, J. and A. Basten (1973). Circulating T and B lymphocytes of the mouse, II. Lifespan. Cell. Immunol. 7, 10–39.

    Article  Google Scholar 

  • Stafford, M., L. Corey, Y. Cao, E. Daar, D. Ho and A. Perelson (2000). Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203, 285–301.

    Article  Google Scholar 

  • Telenti, A. and G. Rizzardi (2000). Limits to potent antiretroviral therapy. Rev. Med. Virol. 10, 385–393.

    Article  Google Scholar 

  • Tremblay, C. et al. (2003). Antiretroviral resistance associated with supervised treatment interruptions in treated acute HIV infection. AIDS 17, 1086–1089.

    Article  Google Scholar 

  • Vella, S. and L. Palmisano (2000). Antiretroviral therapy: state of the HAART. Antiviral Res. 45, 1–7.

    Article  Google Scholar 

  • Wang, L., J. Chen, B. Gelman, R. Konig and M. Cloyd (1999). A novel mechanisms of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph ode homing and apoptosis upon secondary signaling through homing receptors. J. Immunol. 162, 268–276.

    Google Scholar 

  • Yu, X., M. Addo, E. Rosenberg, W. Rodriguez, P. Lee, C. Fitzpatrick, M. Johnston, D. Strick, P. Goulder, B. Walker and M. Altfeld (2002). Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV)-1-specific CD8+ T-cell responses following acute HIV-1 infection. J. Virol. 76, 8690–8701.

    Article  Google Scholar 

  • Zhang, Z. et al. (1998). Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc. Natl. Acad. Sci. 95, 1154–1159.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Department of Biomedical Engineering, The University of Michigan Medical School, Ann Arbor, MI, 48109-0620, USA

    Seema H. Bajaria

  2. Department of Mathematics, Vanderbilt University, Nashville, TN, 37240-0001, USA

    Glenn Webb

  3. Department of Microbiology and Immunology, The University of Michigan Medical School, 6730 Medical Science Building II, Ann Arbor, MI, 48109-0620, USA

    Denise E. Kirschner

Authors
  1. Seema H. Bajaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glenn Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denise E. Kirschner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Denise E. Kirschner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bajaria, S.H., Webb, G. & Kirschner, D.E. Predicting differential responses to structured treatment interruptions during HAART. Bull. Math. Biol. 66, 1093–1118 (2004). https://doi.org/10.1016/j.bulm.2003.11.003

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.bulm.2003.11.003

Keywords

Search

Navigation