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Proc Biol Sci. Feb 7, 2001; 268(1464): 235–242.
PMCID: PMC1088597

Small variations in multiple parameters account for wide variations in HIV-1 set-points: a novel modelling approach.

Abstract

Steady-state levels of HIV-1 viraemia in the plasma vary more than a 1,000-fold between HIV-positive patients and are thought to be influenced by several different host and viral factors such as host target cell availability, host anti-HIV immune response and the virulence of the virus. Previous mathematical models have taken the form of classical ecological food-chain models and are unable to account for this multifactorial nature of the disease. These models suggest that the steady-state viral load (i.e. the set-point) is determined by immune response parameters only. We have devised a generalized consensus model in which the conventional parameters are replaced by so-called 'process functions'. This very general approach yields results that are insensitive to the precise form of the mathematical model. Here we applied the approach to HIV-1 infections by estimating the steady-state values of several process functions from published patient data. Importantly, these estimates are generic because they are independent of the precise form of the underlying processes. We recorded the variation in the estimated steady-state values of the process functions in a group of HIV-1 patients. We developed a novel model by providing explicit expressions for the process functions having the highest patient-to-patient variation in their estimated values. Small variations from patient to patient for several parameters of the new model collectively accounted for the large variations observed in the steady-state viral burden. The novel model remains in full agreement with previous models and data.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bonhoeffer S, Coffin JM, Nowak MA. Human immunodeficiency virus drug therapy and virus load. J Virol. 1997 Apr;71(4):3275–3278. [PMC free article] [PubMed]
  • Bonhoeffer S, May RM, Shaw GM, Nowak MA. Virus dynamics and drug therapy. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6971–6976. [PMC free article] [PubMed]
  • Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994 Sep;68(9):6103–6110. [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]
  • Cavert W, Notermans DW, Staskus K, Wietgrefe SW, Zupancic M, Gebhard K, Henry K, Zhang ZQ, Mills R, McDade H, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science. 1997 May 9;276(5314):960–964. [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]
  • Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science. 1995 Nov 10;270(5238):988–991. [PubMed]
  • De Boer RJ, Perelson AS. Target cell limited and immune control models of HIV infection: a comparison. J Theor Biol. 1998 Feb 7;190(3):201–214. [PubMed]
  • De Boer RJ, Boucher CA, Perelson AS. Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine. AIDS. 1998 Sep 10;12(13):1567–1570. [PubMed]
  • Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, Haase AT. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. [PubMed]
  • Fauci AS. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. [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]
  • 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]
  • Haase AT, Henry K, Zupancic M, Sedgewick G, Faust RA, Melroe H, Cavert W, Gebhard K, Staskus K, Zhang ZQ, et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science. 1996 Nov 8;274(5289):985–989. [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]
  • Hockett RD, Kilby JM, Derdeyn CA, Saag MS, Sillers M, Squires K, Chiz S, Nowak MA, Shaw GM, Bucy RP. Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. J Exp Med. 1999 May 17;189(10):1545–1554. [PMC free article] [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]
  • Katzenstein TL, Pedersen C, Nielsen C, Lundgren JD, Jakobsen PH, Gerstoft J. Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome. AIDS. 1996 Feb;10(2):167–173. [PubMed]
  • McLean AR, Nowak MA. Competition between zidovudine-sensitive and zidovudine-resistant strains of HIV. AIDS. 1992 Jan;6(1):71–79. [PubMed]
  • McLean AR, Emery VC, Webster A, Griffiths PD. Population dynamics of HIV within an individual after treatment with zidovudine. AIDS. 1991 May;5(5):485–489. [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, Markowitz M, Ho DD, Perelson AS. Improved estimates for HIV-1 clearance rate and intracellular delay. AIDS. 1999 Jul 30;13(11):1415–1417. [PubMed]
  • Mori K, Yasutomi Y, Sawada S, Villinger F, Sugama K, Rosenwith B, Heeney JL, Uberla K, Yamazaki S, Ansari AA, et al. Suppression of acute viremia by short-term postexposure prophylaxis of simian/human immunodeficiency virus SHIV-RT-infected monkeys with a novel reverse transcriptase inhibitor (GW420867) allows for development of potent antiviral immune responses resulting in efficient containment of infection. J Virol. 2000 Jul;74(13):5747–5753. [PMC free article] [PubMed]
  • Notermans DW, Goudsmit J, Danner SA, de Wolf F, Perelson AS, Mittler J. Rate of HIV-1 decline following antiretroviral therapy is related to viral load at baseline and drug regimen. AIDS. 1998 Aug 20;12(12):1483–1490. [PubMed]
  • Nowak MA, Bangham CR. Population dynamics of immune responses to persistent viruses. Science. 1996 Apr 5;272(5258):74–79. [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]
  • Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, Sontag G, Sewell AK, Phillips RE. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3382–3387. [PMC free article] [PubMed]
  • Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. [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]
  • Piatak M, Jr, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, Hahn BH, Shaw GM, Lifson JD. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993 Mar 19;259(5102):1749–1754. [PubMed]
  • Ramratnam B, Bonhoeffer S, Binley J, Hurley A, Zhang L, Mittler JE, Markowitz M, Moore JP, Perelson AS, Ho DD. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet. 1999 Nov 20;354(9192):1782–1785. [PubMed]
  • Rinaldo C, Huang XL, Fan ZF, Ding M, Beltz L, Logar A, Panicali D, Mazzara G, Liebmann J, Cottrill M, et al. High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J Virol. 1995 Sep;69(9):5838–5842. [PMC free article] [PubMed]
  • Rosenzweig ML. Paradox of enrichment: destabilization of exploitation ecosystems in ecological time. Science. 1971 Jan 29;171(3969):385–387. [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]
  • Stilianakis NI, Boucher CA, De Jong MD, Van Leeuwen R, Schuurman R, De Boer RJ. Clinical data sets of human immunodeficiency virus type 1 reverse transcriptase-resistant mutants explained by a mathematical model. J Virol. 1997 Jan;71(1):161–168. [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]
  • Weiss RA. How does HIV cause AIDS? Science. 1993 May 28;260(5112):1273–1279. [PubMed]

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