1887

Abstract

Many aspects of the complex interaction between human immunodeficiency virus type 1 (HIV-1) and the human immune system remain elusive. Our objective was to study these interactions, focusing on the specific roles of dendritic cells (DCs). DCs enhance HIV-1 infection processes as well as promote an antiviral immune response. We explored the implications of these dual roles. A mathematical model describing the dynamics of HIV-1, CD4 and CD8 T-cells, and DCs interacting in a human lymph node was analysed and is presented here. We have validated the behaviour of our model against non-human primate simian immunodeficiency virus experimental data and published human HIV-1 data. Our model qualitatively and quantitatively recapitulates clinical HIV-1 infection dynamics. We have performed sensitivity analyses on the model to determine which mechanisms strongly affect infection dynamics. Sensitivity analysis identifies system interactions that contribute to infection progression, including DC-related mechanisms. We have compared DC-dependent and -independent routes of CD4 T-cell infection. The model predicted that simultaneous priming and infection of T cells by DCs drives early infection dynamics when activated T-helper cell numbers are low. Further, our model predicted that, while direct failure of DC function and an indirect failure due to loss of CD4 T-helper cells are both significant contributors to infection dynamics, the former has a more significant impact on HIV-1 immunopathogenesis.

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2008-09-01
2020-10-26
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References

  1. Arrighi J. F., Pion M., Garcia E., Escola J. M., van Kooyk Y., Geijtenbeek T. B., Piguet V. 2004; DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med 200:1279–1288 [CrossRef]
    [Google Scholar]
  2. Bajaria S. H., Kirschner D. 2005; CTL action during HIV-1 is determined via interactions with multiple cell types. In Deterministic and Stochastic Models for AIDS Epidemics and HIV Infection with Interventions pp 219–254Edited by Tan W. Y., Wu. River Edge, NJ: World Scientific;
    [Google Scholar]
  3. Bajaria S. H., Webb G., Cloyd M., Kirschner D. 2002; Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression. J Acquir Immune Defic Syndr 30:41–58 [CrossRef]
    [Google Scholar]
  4. Biancotto A., Grivel J. C., Iglehart S. J., Vanpouille C., Lisco A., Sieg S. F., Debernardo R., Garate K., Rodriguez B. other authors 2007 Abnormal Activation and Cytokine Spectra in Lymph Nodes of Persons Chronically Infected with HIV-1. Blood
    [Google Scholar]
  5. Blauvelt A., Asada H., Saville M. W., Klaus-Kovtun V., Altman D. J., Yarchoan R., Katz S. I. 1997; Productive infection of dendritic cells by HIV-1 and their ability to capture virus are mediated through separate pathways. J Clin Invest 100:2043–2053 [CrossRef]
    [Google Scholar]
  6. Blower S. M., Dowlatabadi H. 1994; Sensitivity and uncertainty analysis of complex models of disease transmission: an HIV model, as an example. Int Stat Rev 62:229–243 [CrossRef]
    [Google Scholar]
  7. Brown K. N., Trichel A., Barratt-Boyes S. M. 2007; Parallel loss of myeloid and plasmacytoid dendritic cells from blood and lymphoid tissue in simian AIDS. J Immunol 178:6958–6967 [CrossRef]
    [Google Scholar]
  8. Bukczynski J., Wen T., Wang C., Christie N., Routy J. P., Boulassel M. R., Kovacs C. M., Macdonald K. S., Ostrowski M. other authors 2005; Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L. J Immunol 175:6378–6389 [CrossRef]
    [Google Scholar]
  9. Cavert W., Notermans D. W., Staskus K., Wietgrefe S. W., Zupancic M., Gebhard K., Henry K., Zhang Z. Q., Mills R. other authors 1997; Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276:960–964 [CrossRef]
    [Google Scholar]
  10. Chougnet C., Gessani S. 2006; Role of gp120 in dendritic cell dysfunction in HIV infection. J Leukoc Biol 80:994–1000 [CrossRef]
    [Google Scholar]
  11. Cohen S. S., Li C., Ding L., Cao Y., Pardee A. B., Shevach E. M., Cohen D. I. 1999; Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge. Proc Natl Acad Sci U S A 96:10842–10847 [CrossRef]
    [Google Scholar]
  12. Cohen Stuart J. W., Hazebergh M. D., Hamann D., Otto S. A., Borleffs J. C., Miedema F., Boucher C. A., de Boer R. J. 2000; The dominant source of CD4+ and CD8+ T-cell activation in HIV infection is antigenic stimulation. J Acquir Immune Defic Syndr 25:203–211 [CrossRef]
    [Google Scholar]
  13. Curran-Everett D. 2000; Multiple comparisons: philosophies and illustrations. Am J Physiol Regul Integr Comp Physiol 279:R1–R8
    [Google Scholar]
  14. Dioszeghy V., Benlhassan-Chahour K., Delache B., Dereuddre-Bosquet N., Aubenque C., Gras G., Le Grand R., Vaslin B. 2006; Changes in soluble factor-mediated CD8+ cell-derived antiviral activity in cynomolgus macaques infected with simian immunodeficiency virus SIVmac251: relationship to biological markers of progression. J Virol 80:236–245 [CrossRef]
    [Google Scholar]
  15. Doherty P. C., Christensen J. P. 2000; Accessing complexity: the dynamics of virus-specific T cell responses. Annu Rev Immunol 18:561–592 [CrossRef]
    [Google Scholar]
  16. Fallert B. A., Reinhart T. A. 2002; Improved detection of simian immunodeficiency virus RNA by in situ hybridization in fixed tissue sections: combined effects of temperatures for tissue fixation and probe hybridization. J Virol Methods 99:23–32 [CrossRef]
    [Google Scholar]
  17. Geiben-Lynn R. 2002; Anti-human immunodeficiency virus noncytolytic CD8+ T-cell response: a review. AIDS Patient Care STDS 16:471–477 [CrossRef]
    [Google Scholar]
  18. Gorry P. R., Sterjovski J., Churchill M., Witlox K., Gray L., Cunningham A., Wesselingh S. 2004; The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression. Sex Health 1:23–34 [CrossRef]
    [Google Scholar]
  19. Granelli-Piperno A., Golebiowska A., Trumpfheller C., Siegal F. P., Steinman R. M. 2004; HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci U S A 101:7669–7674 [CrossRef]
    [Google Scholar]
  20. Haase A. T. 1999; Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol 17:625–656 [CrossRef]
    [Google Scholar]
  21. Hazenberg M. D., Stuart J. W., Otto S. A., Borleffs J. C., Boucher C. A., de Boer R. J., Miedema F., Hamann D. 2000; 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 95:249–255
    [Google Scholar]
  22. Ho D. D. 1996; Viral counts count in HIV infection. Science 272:1124–1125 [CrossRef]
    [Google Scholar]
  23. Janeway C. 2005 Immunobiology: The Immune System in Health and Disease, 6th edn. New York: Garland Science;
    [Google Scholar]
  24. Janssen E. M., Lemmens E. E., Wolfe T., Christen U., von Herrath M. G., Schoenberger S. P. 2003; CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852–856 [CrossRef]
    [Google Scholar]
  25. Jekle A., Keppler O. T., De Clercq E., Schols D., Weinstein M., Goldsmith M. A. 2003; In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells. J Virol 77:5846–5854 [CrossRef]
    [Google Scholar]
  26. Jin X., Bauer D. E., Tuttleton S. E., Lewin S., Gettie A., Blanchard J., Irwin C. E., Safrit J. T., Mittler J. other authors 1999; Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189:991–998 [CrossRef]
    [Google Scholar]
  27. Kedzierska K., Crowe S. M. 2001; Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother 12:133–150 [CrossRef]
    [Google Scholar]
  28. Kitano H., Oda K. 2006; Robustness trade-offs and host-microbial symbiosis in the immune system. Mol Syst Biol 2:0022
    [Google Scholar]
  29. Krathwohl M. D., Schacker T. W., Anderson J. L. 2006; Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects. J Infect Dis 193:494–504 [CrossRef]
    [Google Scholar]
  30. Kwon D. S., Gregorio G., Bitton N., Hendrickson W. A., Littman D. R. 2002; DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16:135–144 [CrossRef]
    [Google Scholar]
  31. Lekkerkerker A. N., van Kooyk Y., Geijtenbeek T. B. 2006; Viral piracy: HIV-1 targets dendritic cells for transmission. Curr HIV Res 4:169–176 [CrossRef]
    [Google Scholar]
  32. Levy J. A. 2003; The search for the CD8+ cell anti-HIV factor (CAF). Trends Immunol 24:628–632 [CrossRef]
    [Google Scholar]
  33. Margolick J. B., Gange S. J., Detels R., O'Gorman M. R., Rinaldo C. R. Jr, Lai S. 2006; Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection. J Acquir Immune Defic Syndr 42:620–626 [CrossRef]
    [Google Scholar]
  34. Marino S., Hogue I. B., Ray C. J., Kirschner D. E. 2008; A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol in press).
    [Google Scholar]
  35. Matano T., Shibata R., Siemon C., Connors M., Lane H. C., Martin M. A. 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
    [Google Scholar]
  36. McDonald D., Wu L., Bohks S. M., KewalRamani V. N., Unutmaz D., Hope T. J. 2003; Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300:1295–1297 [CrossRef]
    [Google Scholar]
  37. Mellman I., Steinman R. M. 2001; Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258 [CrossRef]
    [Google Scholar]
  38. Meng X., Rosenthal R., Rubin D. B. 1992; Comparing correlated correlation coefficients. Psychol Bull 111:172–175 [CrossRef]
    [Google Scholar]
  39. Murphey-Corb M., Martin L. N., Rangan S. R., Baskin G. B., Gormus B. J., Wolf R. H., Andes W. A., West M., Montelaro R. C. 1986; Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature 321:435–437 [CrossRef]
    [Google Scholar]
  40. Pitcher C. J., Hagen S. I., Walker J. M., Lum R., Mitchell B. L., Maino V. C., Axthelm M. K., Picker L. J. 2002; Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168:29–43 [CrossRef]
    [Google Scholar]
  41. Poli G., Pantaleo G., Fauci A. S. 1993; Immunopathogenesis of human immunodeficiency virus infection. Clin Infect Dis 17:Suppl. 1S224–S229 [CrossRef]
    [Google Scholar]
  42. Reimann K. A., Parker R. A., Seaman M. S., Beaudry K., Beddall M., Peterson L., Williams K. C., Veazey R. S., Montefiori D. C. other authors 2005; Pathogenicity of simian-human immunodeficiency virus SHIV-89.6P and SIVmac is attenuated in cynomolgus macaques and associated with early T-lymphocyte responses. J Virol 79:8878–8885 [CrossRef]
    [Google Scholar]
  43. Reinhart T. A., Fallert B. A., Pfeifer M. E., Sanghavi S., Capuano S. III, Rajakumar P., Murphey-Corb M., Day R., Fuller C. L., Schaefer T. M. 2002; Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. Blood 99:3119–3128 [CrossRef]
    [Google Scholar]
  44. Ridge J. P., Di Rosa F., Matzinger P. 1998; A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478 [CrossRef]
    [Google Scholar]
  45. Riggs T., Walts A., Perry N., Bickle L., Lynch J. N., Myers A., Flynn J., Linderman J. J., Miller M. J., Kirschner D. E. 2008; A comparison of random vs. chemotaxis-driven contacts of T cells with dendritic cells during repertoire scanning. J Theor Biol 250:732–751 [CrossRef]
    [Google Scholar]
  46. Ronchese F., Hermans I. F. 2001; Killing of dendritic cells: a life cut short or a purposeful death?. J Exp Med 194:F23–F26 [CrossRef]
    [Google Scholar]
  47. Ruedl C., Koebel P., Bachmann M., Hess M., Karjalainen K. 2000; Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J Immunol 165:4910–4916 [CrossRef]
    [Google Scholar]
  48. Saltelli A., Tarantola S., Chan K. P.-S. 1999; A quantitative model-independent method for global sensitivity analysis of model output. Technometrics 41:39–56 [CrossRef]
    [Google Scholar]
  49. Schmitz J. E., Kuroda M. J., Santra S., Sasseville V. G., Simon M. A., Lifton M. A., Racz P., Tenner-Racz K., Dalesandro M. other authors 1999; Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–860 [CrossRef]
    [Google Scholar]
  50. Schoenberger S. P., Toes R. E., van der Voort E. I., Offringa R., Melief C. J. 1998; T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393:480–483 [CrossRef]
    [Google Scholar]
  51. Serre K., Giraudo L., Siret C., Leserman L., Machy P. 2006; CD4 T cell help is required for primary CD8 T cell responses to vesicular antigen delivered to dendritic cells in vivo. Eur J Immunol 36:1386–1397 [CrossRef]
    [Google Scholar]
  52. Shampine L. F., Reichelt M. W. 1997; The matlab ode Suite. SIAM J Sci Comput 18:1–22 [CrossRef]
    [Google Scholar]
  53. Shedlock D. J., Shen H. 2003; Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300:337–339 [CrossRef]
    [Google Scholar]
  54. Smith C. M., Wilson N. S., Waithman J., Villadangos J. A., Carbone F. R., Heath W. R., Belz G. T. 2004; Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat Immunol 5:1143–1148 [CrossRef]
    [Google Scholar]
  55. Sol-Foulon N., Moris A., Nobile C., Boccaccio C., Engering A., Abastado J. P., Heard J. M., van Kooyk Y., Schwartz O. 2002; HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity 16:145–155 [CrossRef]
    [Google Scholar]
  56. Steinman R. M. 1991; The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296 [CrossRef]
    [Google Scholar]
  57. Stilianakis N. I., Dietz K., Schenzle D. 1997; Analysis of a model for the pathogenesis of AIDS. Math Biosci 145:27–46 [CrossRef]
    [Google Scholar]
  58. Trepel F. 1974; Number and distribution of lymphocytes in man. A critical analysis. Klin Wochenschr 52:511–515 [CrossRef]
    [Google Scholar]
  59. Turville S. G., Cameron P. U., Handley A., Lin G., Pohlmann S., Doms R. W., Cunningham A. L. 2002; Diversity of receptors binding HIV on dendritic cell subsets. Nat Immunol 3:975–983 [CrossRef]
    [Google Scholar]
  60. von Andrian U. H., Mempel T. R. 2003; Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3:867–878 [CrossRef]
    [Google Scholar]
  61. Wang J. C., Livingstone A. M. 2003; Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo . J Immunol 171:6339–6343 [CrossRef]
    [Google Scholar]
  62. Whitmire J. K., Ahmed R. 2000; Costimulation in antiviral immunity: differential requirements for CD4+ and CD8+ T cell responses. Curr Opin Immunol 12:448–455 [CrossRef]
    [Google Scholar]
  63. Wilson N. S., Villadangos J. A. 2004; Lymphoid organ dendritic cells: beyond the Langerhans cells paradigm. Immunol Cell Biol 82:91–98 [CrossRef]
    [Google Scholar]
  64. Wodarz D., Nowak M. A. 2002; Mathematical models of HIV pathogenesis and treatment. Bioessays 24:1178–1187 [CrossRef]
    [Google Scholar]
  65. Xiao L., Rudolph D. L., Owen S. M., Spira T. J., Lal R. B. 1998; Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression. AIDS 12:F137–F143 [CrossRef]
    [Google Scholar]
  66. Yang J., Huck S. P., McHugh R. S., Hermans I. F., Ronchese F. 2006; Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo . Proc Natl Acad Sci U S A 103:147–152 [CrossRef]
    [Google Scholar]
  67. Zhang Z. Q., Wietgrefe S. W., Li Q., Shore M. D., Duan L., Reilly C., Lifson J. D., Haase A. T. 2004; Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc Natl Acad Sci U S A 101:5640–5645 [CrossRef]
    [Google Scholar]
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