Abstract
The combination of mathematical modelling and data analysis to understand the within-host dynamics of human immunodeficiency virus (HIV) infections has been one of the most informative uses of mathematical biology in the last decade. Simple models of viral dynamics together with viral load measurements provided an early estimate that the turnover of HIV infected cells is very rapid: most do not survive beyond 1 day. Although this estimate was initially a surprise to the field, further corroborating evidence has made it widely accepted. More recently, within-host models have been used to investigate the efficacy of cytotoxic T-lymphocytes (CTLs) in controlling HIV infection. Though there is clear experimental evidence that they play some role, the magnitude of this role remains contentious. Models have offered three insights on this topic. Firstly, in chronically infected humans fewer than 20% of HIV-infected cell death is attributed to killing by CTLs. Secondly, CTLs are more efficient in acute infection than chronic infection, but not dramatically so, and thirdly, CTLs are markedly more efficient in simian than human immunodeficiency viral infection. Although based on simple models and repeatable data, the main prediction of this work that CTL vaccines might work in macaques but not in humans is yet to gain recognition. This is despite the fact that this prediction was borne out by the failure of STEP vaccine. We contend that in time this assertion too will become more widely accepted.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
UNAIDS (2008) 2008 Report on global AIDS epidemic.
Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF (2005) Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 191:654–665
Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) Virus-specific CD8 + cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68:6103–6110
Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68:4650–4655
Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, Meyers H, Nelson JA, Gairin JE, Hahn BH, Oldstone MB, Shaw GM (1997) Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nature 3:205–211
Price DA, Goulder PJ, Klenerman P, Sewell AK, Easterbrook PJ, Troop M, Bangham CR, Phillips RE (1997) Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci USA 94:1890–1895
Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O’Brien SJ (1999) HLA and HIV-1: heterozygote advantage and b*35-cw*04 disadvantage. Science 283:1748–1752
Gao X, Nelson GW, Karacki P, Martin MP, Phair J, Kaslow R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, O’Brien SJ, Carrington M (2001) Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 344:1668–1675
Carrington M, O’Brien SJ (2003) The influence of HLA genotype on AIDS. Annu Rev Med 54:535–551
Cohen J (2007) AIDS research. Did Merck’s failed HIV vaccine cause harm? Science 318:1048–1049
Cohen J (2007) AIDS research. Promising AIDS vaccine’s failure leaves field reeling. Science 318:28–29
Shiver JW, Fu TM, Chen L, Casimiro DR, Davies ME, Evans RK, Zhang ZQ, Simon AJ, Trigona WL, Dubey SA, Huang L, Harris VA, Long RS, Liang X, Handt L, Schleif WA, Zhu L, Freed DC, Persaud NV, Guan L, Punt KS, Tang A, Chen M, Wilson KA, Collins KB, Heidecker GJ, Fernandez VR, Perry HC, Joyce JG, Grimm KM, Cook JC, Keller PM, Kresock DS, Mach H, Troutman RD, Isopi LA, Williams DM, Xu Z, Bohannon KE, Volkin DB, Montefiori DC, Miura A, Krivulka GR, Lifton MA, Kuroda MJ, Schmitz JE, Letvin NL, Caulfield MJ, Bett AJ, Youil R, Kaslow DC, Emini EA (2002) Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415:331–335
Asquith B, Edwards CT, Lipsitch M, McLean AR (2006) Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo. PLoS Biol 4:e90
Asquith B, McLean AR (2007) In vivo CD8 + T cell control of immunodeficiency virus infection in humans and macaques. Proc Natl Acad Sci USA 104:6365–6370
HVTN (2007) The step study. Summary. Press briefing. November 7, 2007
Walker BD, Chakrabarti S, Moss B, Paradis TJ, Flynn T, Durno AG, Blumberg RS, Kaplan JC, Hirsch MS, Schooley RT (1987) HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature 328:345–348
Buseyne F, Fevrier M, Garcia S, Gougeon ML, Riviere Y (1996) Dual function of a human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte clone: inhibition of HIV replication by noncytolytic mechanisms and lysis of HIV-infected CD4 + cells. Virology 225:248–253
Yang OO, Kalams SA, Trocha A, Cao H, Luster A, Johnson RP, Walker BD (1997) Suppression of human immunodeficiency virus type 1 replication by CD8 + cells: evidence for HLA class i-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol 71:3120–3128
Van Baalen CA, Schutten M, Huisman RC, Boers PH, Gruters RA, Osterhaus AD (1998) Kinetics of antiviral activity by human immunodeficiency virus type 1-specific cytotoxic T lymphocytes (CTL) and rapid selection of CTL escape virus in vitro. J Virol 72:6851–6857
Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA (1998) Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72:164–169
Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD (1999) Dramatic rise in plasma viremia after CD8 + T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189:991–998
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA (1999) Control of viremia in simian immunodeficiency virus infection by CD8 + lymphocytes. Science 283:857–860
Harrer T, Harrer E, Kalams SA, Elbeik T, Staprans SI, Feinberg MB, Cao Y, Ho DD, Yilma T, Caliendo AM, Johnson RP, Buchbinder SP, Walker BD (1996) 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 12:585–592
Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, Segal JP, Cao Y, Rowland-Jones SL, Cerundolo V, Hurley A, Markowitz M, Ho DD, Nixon DF, McMichael AJ (1998) Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279:2103–2106
Edwards BH, Bansal A, Sabbaj S, Bakari J, Mulligan MJ, Goepfert PA (2002) Magnitude of functional CD8 + T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J Virol 76:2298–2305
Oxenius A, McLean AR, Fischer M, Price DA, Dawson SJ, Hafner R, Schneider C, Joller H, Hirschel B, Phillips RE, Weber R, Gunthard HF (2002) Human immunodeficiency virus-specific CD8 + t-cell responses do not predict viral growth and clearance rates during structured intermittent antiretroviral therapy. J Virol 76:10169–10176
Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D, Johnston MN, Corcoran C, Wurcel AG, Fitzpatrick CA, Feeney ME, Rodriguez WR, Basgoz N, Draenert R, Stone DR, Brander C, Goulder PJ, Rosenberg ES, Altfeld M, Walker BD (2003) Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 77:2081–2092
Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, Bishop K, van der Stok M, Nair K, Khan N, Crawford H, Payne R, Leslie A, Prado J, Prendergast A, Frater J, McCarthy N, Brander C, Learn GH, Nickle D, Rousseau C, Coovadia H, Mullins JI, Heckerman D, Walker BD, Goulder P (2007) CD8 + t-cell responses to different HIV proteins have discordant associations with viral load. Nature 13:46–53
Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8 + T cells. Blood 107:4781–4789
Daucher M, Price DA, Brenchley JM, Lamoreaux L, Metcalf JA, Rehm C, Nies-Kraske E, Urban E, Yoder C, Rock D, Gumkowski J, Betts MR, Dybul MR, Douek DC (2008) Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8 + T cells. J Virol 82:4102–4114
McMichael AJ, Phillips RE (1997) Escape of human immunodeficiency virus from immune control. Annu Rev Immunol 15:271–296
Perelson AS (2002) Modelling viral and immune system dynamics. Nature 2:28–36
Phillips AN (1996) Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271:497–499
Stafford MA, Corey L, Cao Y, Daar ES, Ho DD, Perelson AS (2000) Modeling plasma virus concentration during primary HIV infection. J Theor Biol 203:285–301
Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271:1582–1586
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–126
Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373:117–122
Rodrigo AG, Shpaer EG, Delwart EL, Iversen AK, Gallo MV, Brojatsch J, Hirsch MS, Walker BD, Mullins JI (1999) Coalescent estimates of HIV-1 generation time in vivo. Proc Natl Acad Sci USA 96:2187–2191
Macallan DC, Asquith B, Irvine AJ, Wallace DL, Worth A, Ghattas H, Zhang Y, Griffin GE, Tough DF, Beverley PC (2003) Measurement and modeling of human T cell kinetics. Eur J Immunol 33:2316–2326
Markowitz M, Louie M, Hurley A, Sun E, Di Mascio M, Perelson AS, Ho DD (2003) A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and t-cell decay in vivo. J Virol 77:5037–5038
Friedrich TC, Dodds EJ, Yant LJ, Vojnov L, Rudersdorf R, Cullen C, Evans DT, Desrosiers RC, Mothe BR, Sidney J, Sette A, Kunstman K, Wolinsky S, Piatak M, Lifson J, Hughes AL, Wilson N, O’Connor DH, Watkins DI (2004) Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nature 10:275–281
Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M, Tang Y, Holmes EC, Allen T, Prado JG, Altfeld M, Brander C, Dixon C, Ramduth D, Jeena P, Thomas SA, St John A, Roach TA, Kupfer B, Luzzi G, Edwards A, Taylor G, Lyall H, Tudor-Williams G, Novelli V, Martinez-Picado J, Kiepiela P, Walker BD, Goulder PJ (2004) HIV evolution: CTL escape mutation and reversion after transmission. Nature 10:282–289
Draenert R, Le Gall S, Pfafferott KJ, Leslie AJ, Chetty P, Brander C, Holmes EC, Chang SC, Feeney ME, Addo MM, Ruiz L, Ramduth D, Jeena P, Altfeld M, Thomas S, Tang Y, Verrill CL, Dixon C, Prado JG, Kiepiela P, Martinez-Picado J, Walker BD, Goulder PJ (2004) Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J Exp Med 199:905–915
Goulder PJ, Brander C, Tang Y, Tremblay C, Colbert RA, Addo MM, Rosenberg ES, Nguyen T, Allen R, Trocha A, Altfeld M, He S, Bunce M, Funkhouser R, Pelton SI, Burchett SK, McIntosh K, Korber BT, Walker BD (2001) Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412:334–338
Moore CB, John M, James IR, Christiansen FT, Witt CS, Mallal SA (2002) Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296:1439–1443
Kawashima Y, Pfafferott K, Frater J, Matthews P, Payne R, Addo M, Gatanaga H, Fujiwara M, Hachiya A, Koizumi H, Kuse N, Oka S, Duda A, Prendergast A, Crawford H, Leslie A, Brumme Z, Brumme C, Allen T, Brander C, Kaslow R, Tang J, Hunter E, Allen S, Mulenga J, Branch S, Roach T, John M, Mallal S, Ogwu A, Shapiro R, Prado JG, Fidler S, Weber J, Pybus OG, Klenerman P, Ndung’u T, Phillips R, Heckerman D, Harrigan PR, Walker BD, Takiguchi M, Goulder P (2009) Adaptation of HIV-1 to human leukocyte antigen class i. Nature 458: 641–645
Frahm N, Korber BT, Adams CM, Szinger JJ, Draenert R, Addo MM, Feeney ME, Yusim K, Sango K, Brown NV, SenGupta D, Piechocka-Trocha A, Simonis T, Marincola FM, Wurcel AG, Stone DR, Russell CJ, Adolf P, Cohen D, Roach T, StJohn A, Khatri A, Davis K, Mullins J, Goulder PJ, Walker BD, Brander C (2004) Consistent cytotoxic-t-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities. J Virol 78:2187–2200
Geels MJ, Cornelissen M, Schuitemaker H, Anderson K, Kwa D, Maas J, Dekker JT, Baan E, Zorgdrager F, van den Burg R, van Beelen M, Lukashov VV, Fu TM, Paxton WA, van der Hoek L, Dubey SA, Shiver JW, Goudsmit J (2003) Identification of sequential viral escape mutants associated with altered t-cell responses in a human immunodeficiency virus type 1-infected individual. J Virol 77:12430–12440
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Fryer, H., McLean, A. (2011). Using Mathematical Models to Explore the Role of Cytotoxic T Lymphocytes in HIV Infection. In: Molina-París, C., Lythe, G. (eds) Mathematical Models and Immune Cell Biology. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7725-0_18
Download citation
DOI: https://doi.org/10.1007/978-1-4419-7725-0_18
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-7724-3
Online ISBN: 978-1-4419-7725-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)