Search tips
Search criteria 


Logo of transbThe Royal Society PublishingPhilosophical Transactions BAboutBrowse By SubjectAlertsFree Trial
Philos Trans R Soc Lond B Biol Sci. 2000 August 29; 355(1400): 1059–1070.
PMCID: PMC1692817

Correlates of cytotoxic T-lymphocyte-mediated virus control: implications for immunosuppressive infections and their treatment.


A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarizes how mathematical models help us gain new insights into these questions, and explores the relationship between antiviral therapy and long-term immunological control in human immunodeficiency virus (HIV) infection. We find that cytotoxic T lymphocyte (CTL) memory, defined as antigen-independent persistence of CTL precursors, is necessary for the CTL response to clear an infection. The presence of such a memory response is associated with the coexistence of many CTL clones directed against multiple epitopes. If CTL memory is inefficient, then persistent replication can be established. This outcome is associated with a narrow CTL response directed against only one or a few viral epitopes. If the virus replicates persistently, occurrence of pathology depends on the level of virus load at equilibrium, and this can be determined by the overall efficacy of the CTL response. Mathematical models suggest that controlled replication is reflected by a positive correlation between CTLs and virus load. On the other hand, uncontrolled viral replication results in higher loads and the absence of a correlation between CTLs and virus load. A negative correlation between CTLs and virus load indicates that the virus actively impairs immunity, as observed with HIV. Mathematical models and experimental data suggest that HIV persistence and pathology are caused by the absence of sufficient CTL memory. We show how mathematical models can help us devise therapy regimens that can restore CTL memory in HIV patients and result in long-term immunological control of the virus in the absence of life-long treatment.

Full Text

The Full Text of this article is available as a PDF (286K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Borrow P, Tishon A, Lee S, Xu J, Grewal IS, Oldstone MB, Flavell RA. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J Exp Med. 1996 May 1;183(5):2129–2142. [PMC free article] [PubMed]
  • Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, Meyers H, Nelson JA, Gairin JE, Hahn BH, Oldstone MB, et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med. 1997 Feb;3(2):205–211. [PubMed]
  • Borrow P, Tough DF, Eto D, Tishon A, Grewal IS, Sprent J, Flavell RA, Oldstone MB. CD40 ligand-mediated interactions are involved in the generation of memory CD8(+) cytotoxic T lymphocytes (CTL) but are not required for the maintenance of CTL memory following virus infection. J Virol. 1998 Sep;72(9):7440–7449. [PMC free article] [PubMed]
  • Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brien SJ. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999 Mar 12;283(5408):1748–1752. [PubMed]
  • Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193–13197. [PubMed]
  • Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995 Apr 6;374(6522):569–571. [PubMed]
  • Daenke S, Kermode AG, Hall SE, Taylor G, Weber J, Nightingale S, Bangham CR. High activated and memory cytotoxic T-cell responses to HTLV-1 in healthy carriers and patients with tropical spastic paraparesis. Virology. 1996 Mar 1;217(1):139–146. [PubMed]
  • De Boer RJ, Perelson AS. T cell repertoires and competitive exclusion. J Theor Biol. 1994 Aug 21;169(4):375–390. [PubMed]
  • Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997 Nov 14;278(5341):1295–1300. [PubMed]
  • Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, Nowak MA, Giangrande P, Luzzi G, Morgan B, Edwards A, et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med. 1997 Feb;3(2):212–217. [PubMed]
  • Harrer T, Harrer E, Kalams SA, Barbosa P, Trocha A, Johnson RP, Elbeik T, Feinberg MB, Buchbinder SP, Walker BD. Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection. Breadth and specificity of the response and relation to in vivo viral quasispecies in a person with prolonged infection and low viral load. J Immunol. 1996 Apr 1;156(7):2616–2623. [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]
  • Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999 Mar 15;189(6):991–998. [PMC free article] [PubMed]
  • Kalams SA, Walker BD. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J Exp Med. 1998 Dec 21;188(12):2199–2204. [PMC free article] [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]
  • Krakauer DC, Nowak M. T-cell induced pathogenesis in HIV: bystander effects and latent infection. Proc Biol Sci. 1999 May 22;266(1423):1069–1075. [PMC free article] [PubMed]
  • Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. [PubMed]
  • Letvin NL. Progress in the development of an HIV-1 vaccine. Science. 1998 Jun 19;280(5371):1875–1880. [PubMed]
  • Lifson JD, Nowak MA, Goldstein S, Rossio JL, Kinter A, Vasquez G, Wiltrout TA, Brown C, Schneider D, Wahl L, et al. The extent of early viral replication is a critical determinant of the natural history of simian immunodeficiency virus infection. J Virol. 1997 Dec;71(12):9508–9514. [PMC free article] [PubMed]
  • Lisziewicz J, Rosenberg E, Lieberman J, Jessen H, Lopalco L, Siliciano R, Walker B, Lori F. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med. 1999 May 27;340(21):1683–1684. [PubMed]
  • Mellors JW, Kingsley LA, Rinaldo CR, Jr, Todd JA, Hoo BS, Kokka RP, Gupta P. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995 Apr 15;122(8):573–579. [PubMed]
  • Nowak MA, Bangham CR. Population dynamics of immune responses to persistent viruses. Science. 1996 Apr 5;272(5258):74–79. [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]
  • 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]
  • Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, Kuebler PJ, Donahoe SM, Demoitie MA, Kakimoto WM, et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest. 1999 Sep;104(6):R13–R18. [PMC free article] [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]
  • Price DA, Goulder PJ, Klenerman P, Sewell AK, Easterbrook PJ, Troop M, Bangham CR, Phillips RE. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1890–1895. [PubMed]
  • Richman DD. Drug resistance in viruses. Trends Microbiol. 1994 Oct;2(10):401–407. [PubMed]
  • Rosenberg ES, Walker BD. HIV type 1-specific helper T cells: a critical host defense. AIDS Res Hum Retroviruses. 1998 Jun;14 (Suppl 2):S143–S147. [PubMed]
  • Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997 Nov 21;278(5342):1447–1450. [PubMed]
  • Rosenberg ES, LaRosa L, Flynn T, Robbins G, Walker BD. Characterization of HIV-1-specific T-helper cells in acute and chronic infection. Immunol Lett. 1999 Mar;66(1-3):89–93. [PubMed]
  • Saah AJ, Hoover DR, Weng S, Carrington M, Mellors J, Rinaldo CR, Jr, Mann D, Apple R, Phair JP, Detels R, et al. Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study. AIDS. 1998 Nov 12;12(16):2107–2113. [PubMed]
  • Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999 Feb 5;283(5403):857–860. [PubMed]
  • Thomsen AR, Johansen J, Marker O, Christensen JP. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. J Immunol. 1996 Oct 1;157(7):3074–3080. [PubMed]
  • Thomsen AR, Nansen A, Christensen JP, Andreasen SO, Marker O. CD40 ligand is pivotal to efficient control of virus replication in mice infected with lymphocytic choriomeningitis virus. J Immunol. 1998 Nov 1;161(9):4583–4590. [PubMed]
  • Wodarz D, Klenerman P, Nowak MA. Dynamics of cytotoxic T-lymphocyte exhaustion. Proc Biol Sci. 1998 Feb 7;265(1392):191–203. [PMC free article] [PubMed]
  • Zinkernagel RM. Immune protection vs. immunopathology vs. autoimmunity: a question of balance and of knowledge. Brain Pathol. 1993 Apr;3(2):115–121. [PubMed]
  • Zinkernagel RM. Immunology taught by viruses. Science. 1996 Jan 12;271(5246):173–178. [PubMed]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society