1887

Abstract

Engineered therapeutic viruses provide an alternative method for treating infectious diseases, and mathematical models can clarify the system's dynamics underlying this type of therapy. In particular, this study developed models to evaluate the potential to contain human immunodeficiency virus type 1 (HIV-1) infection using a genetically engineered ‘hunter’ virus that kills HIV-1-infected cells. First, we constructed a novel model for understanding the progression of HIV infection that predicted the loss of the immune system's CD4 T cells across time. Subsequently, it determined the effects of introducing hunter viruses in restoring cell population. The model implemented direct and indirect mechanisms by which HIV-1 may cause cell depletion and an immune response. Results suggest that the slow progression of HIV infection may result from a slowly decaying CTL immune response, leading to a limited but constant removal of uninfected CD4 resting cells through apoptosis – and from resting cell proliferation that reduces the rate of cell depletion over time. Importantly, results show that the hunter virus does restrain HIV infection and has the potential to allow major cell recovery to ‘functional’ levels. Further, the hunter virus persisted at a reduced HIV load and was effective either early or late in the infection. This study indicates that hunter viruses may halt the progression of the HIV infection by restoring and sustaining high CD4 T-cell levels.

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2010-10-01
2019-09-18
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References

  1. Ahr, B., Robert-Hebmann, V., Devaux, C. & Biard-Piechaczyk, M. ( 2004; ). Apoptosis of uninfected cells induced by HIV envelope glycoproteins. Retrovirology 1, 1–12.[CrossRef]
    [Google Scholar]
  2. Altes, H. K., Wodarz, D. & Jansen, V. A. A. ( 2002; ). The dual role of CD4 T helper cells in the infection dynamics of HIV and their importance for vaccination. J Theor Biol 214, 633–646.[CrossRef]
    [Google Scholar]
  3. Appay, V., Papagno, L., Spina, C. A., Hansasuta, P., King, A., Jones, L., Ogg, G. S., Little, S., McMichael, A. J. & other authors ( 2002; ). Dynamics of T cell responses in HIV infection. J Immunol 168, 3660–3666.[CrossRef]
    [Google Scholar]
  4. 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]
  5. Betts, M. R., Ambrozak, D. R., Douek, D. C., Bonhoeffer, S., Brenchley, J. M., Casazza, J. P., Koup, R. A. & Picker, L. J. ( 2001; ). Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell responses: relationship to viral load in untreated HIV infection. J Virol 75, 11983–11991.[CrossRef]
    [Google Scholar]
  6. Broussard, S. R., Staprans, S. I., White, R., Whitehead, E. M., Feinberg, M. B. & Allan, J. S. ( 2001; ). Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J Virol 75, 2262–2275.[CrossRef]
    [Google Scholar]
  7. Carlton, R. M. ( 1999; ). Phage therapy: past history and future prospects. Arch Immunol Ther Exp (Warsz) 47, 267–274.
    [Google Scholar]
  8. Cohen, O., Weissman, D. & Fauci, A. S. ( 1999; ). The immunopathogenesis of HIV infection. In Fundamental Immunology, pp. 1455–1509. Edited by Paul, W. E.. Philadelphia, PA. : Lippincott–Raven.
    [Google Scholar]
  9. Concerted Action on SeroConversion to AIDS and Death in Europe ( 2000; ). Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Lancet 355, 1131–1137.[CrossRef]
    [Google Scholar]
  10. Davenport, M. P., Ribeiro, R. M. & Perelson, A. S. ( 2004; ). Kinetics of virus-specific CD8+ T cells and the control of human immunodeficiency virus infection. J Virol 78, 10096–10103.[CrossRef]
    [Google Scholar]
  11. Davis, I. C., Girard, M. & Fultz, P. N. ( 1998; ). Loss of CD4+ T cells in human immunodeficiency virus type 1-infected chimpanzees is associated with increased lymphocyte apoptosis. J Virol 72, 4623–4632.
    [Google Scholar]
  12. De Boer, R. J. & Perelson, A. S. ( 1998; ). Target cell limited and immune control models of HIV infection: a comparison. J Theor Biol 190, 201–214.[CrossRef]
    [Google Scholar]
  13. Di Mascio, M., Sereti, I., Matthews, L. T., Natarajan, V., Adelsberger, J., Lempicki, R., Yoder, C., Jones, E., Chow, C. & other authors ( 2006; ). Naive T-cell dynamics in human immunodeficiency virus type 1 infection: effects of highly active antiretroviral therapy provide insights into the mechanisms of naive T-cell depletion. J Virol 80, 2665–2674.[CrossRef]
    [Google Scholar]
  14. Dimitrov, D. S., Willey, R. L., Sato, H., Chang, L. J., Blumenthal, R. & Martin, M. A. ( 1993; ). Quantitation of human-immunodeficiencvirus type-1infection kinetics. J Virol 67, 2182–2190.
    [Google Scholar]
  15. Douek, D. C., Picker, L. J. & Koup, R. A. ( 2003; ). T cell dynamics in HIV-1 infection. Annu Rev Immunol 21, 265–304.[CrossRef]
    [Google Scholar]
  16. Duffin, R. P. & Tullis, R. H. ( 2002; ). Mathematical models of the complete course of HIV infection and AIDS. Comput Math Methods Med 4, 215–221.
    [Google Scholar]
  17. Fauci, A. & Desrosiers, R. ( 1997; ). Pathogenesis of HIV and SIV. In Retroviruses, pp. 587–636. Edited by Coffin, J. M., Hughes, S. H. & Varmus, H. E.. Plainview, NY. : Cold Spring Harbor Laboratory Press.
    [Google Scholar]
  18. Finkel, T. H., Tudor-Williams, G., Banda, N. K., Cotton, M. F., Curiel, T., Monks, C., Baba, T. W., Ruprecht, R. M. & Kupfer, A. ( 1995; ). Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1, 129–134.[CrossRef]
    [Google Scholar]
  19. Funk, G. A., Fischer, M., Joos, B., Opravil, M., Günthard, H. F., Ledergerber, B. & Bonhoeffer, S. ( 2001; ). Quantification of in vivo replicative capacity of HIV-1 in different compartments of infected cells. J Acquir Immune Defic Syndr 26, 397–404.[CrossRef]
    [Google Scholar]
  20. Geng, E. H. & Deeks, S. G. ( 2009; ). CD4+ T cell recovery with antiretroviral therapy: more than the sum of the parts. Clin Infect Dis 48, 362–364.[CrossRef]
    [Google Scholar]
  21. Gougeon, M. L. ( 2003; ). Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol 3, 392–404.[CrossRef]
    [Google Scholar]
  22. Grossman, Z., Meier-Schellersheim, M., Sousa, A. E., Victorino, R. M. & Paul, W. E. ( 2002; ). CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 8, 319–323.[CrossRef]
    [Google Scholar]
  23. 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]
  24. Hazenberg, M. D., Hamann, D., Schuitemaker, H. & Miedema, F. ( 2000; ). T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol 1, 285–289.[CrossRef]
    [Google Scholar]
  25. Hellerstein, M. K., Hoh, R. A., Hanley, M. B., Cesar, D., Lee, D., Neese, R. A. & McCune, J. M. ( 2003; ). Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest 112, 956–966.[CrossRef]
    [Google Scholar]
  26. Holzammer, S., Holznagel, E., Kaul, A., Kurth, R. & Norley, S. ( 2001; ). High virus loads in naturally and experimentally SIVagm-infected African green monkeys. Virology 283, 324–331.[CrossRef]
    [Google Scholar]
  27. Hunt, P. W., Deeks, S. G., Rodriguez, B., Valdez, H., Shadea, S. B., Abrams, D. I., Kitahata, M. M., Krone, M., Neilands, T. B. & other authors ( 2003; ). Continued CD4 cell count increases in HIV infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 17, 1907–1915.[CrossRef]
    [Google Scholar]
  28. Hunt, P. W., Brenchley, J., Sinclair, E., McCune, J. M., Roland, M., Page-Shafer, K., Hsue, P., Emu, B., Krone, M. & other authors ( 2008; ). Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197, 126–133.[CrossRef]
    [Google Scholar]
  29. Kaufmann, G. R., Zaunders, J., Murray, J., Kelleher, A. D., Lewin, S. R., Solomon, A., Smith, D. & Cooper, D. A. ( 2001; ). Relative significance of different pathways of immune reconstitution in HIV type 1 infection as estimated by mathematical modeling. AIDS Res Hum Retroviruses 17, 147–159.[CrossRef]
    [Google Scholar]
  30. Klenerman, P., Phillips, R. E., Rinaldo, C. R., Wahl, L. M., Ogg, G., May, R. M., McMichael, A. J. & Nowak, M. A. ( 1996; ). Cytotoxic T lymphocytes and viral turnover in HIV type 1 infection. Proc Natl Acad Sci U S A 93, 15323–15328.[CrossRef]
    [Google Scholar]
  31. Layne, S. P., Spouge, J. L. & Dembo, M. ( 1989; ). Quantifying the infectivity of human immunodeficiency virus. Proc Natl Acad Sci U S A 86, 4644–4648.[CrossRef]
    [Google Scholar]
  32. Levin, B. R. & Bull, J. J. ( 1996; ). Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics. Am Nat 147, 881–898.[CrossRef]
    [Google Scholar]
  33. Levine, B. L., Humeau, L. M., Boyer, J., MacGregor, R. R., Rebello, T., Lu, X., Binder, G. K., Slepushkin, V., Lemiale, F. & other authors ( 2006; ). Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A 103, 17372–17377.[CrossRef]
    [Google Scholar]
  34. Lindbäck, S., Karlsson, A. C., Mittler, J., Blaxhult, A., Carlsson, M., Briheim, G., Sönnerborg, A. & Gaines, H. ( 2000; ). Viral dynamics in primary HIV-1 infection. Karolinska Institutet Primary HIV Infection Study Group. AIDS 14, 2283–2291.[CrossRef]
    [Google Scholar]
  35. Liu, J. H. ( 2003; ). A First Course in the Qualitative Theory of Differential Equations. New Jersey. : Prentice Hall.
    [Google Scholar]
  36. Mandl, J. N., Regoes, R. R., Garber, D. A. & Feinberg, M. B. ( 2007; ). Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape. J Virol 81, 11982–11991.[CrossRef]
    [Google Scholar]
  37. Markowitz, M., Louie, M., Hurley, A., Sun, E., Di Mascio, M., Perelson, A. S. & Ho, D. D. ( 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.[CrossRef]
    [Google Scholar]
  38. McCune, J. M. ( 2001; ). The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410, 974–979.[CrossRef]
    [Google Scholar]
  39. McMichael, A. J. & Phillips, R. E. ( 1997; ). Escape of human immunodeficiency virus from immune control. Annu Rev Immunol 15, 271–296.[CrossRef]
    [Google Scholar]
  40. Michie, C. A., McLean, A., Alcock, C. & Beverley, P. C. ( 1992; ). Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265.[CrossRef]
    [Google Scholar]
  41. Morris, K. V., Grahn, R. A., Looney, D. J. & Pedersen, N. C. ( 2004; ). Characterization of a mobilization-competent simian immunodeficiency virus (SIV) vector containing a ribozyme against SIV polymerase. J Gen Virol 85, 1489–1496.[CrossRef]
    [Google Scholar]
  42. Murray, J. M., Kaufmann, G., Kelleher, A. D. & Cooper, D. A. ( 1998; ). A model of primary HIV-1 infection. Math Biosci 154, 57–85.[CrossRef]
    [Google Scholar]
  43. Nelson, G. W. & Perelson, A. S. ( 1995; ). Modeling defective interfering virus therapy for AIDS: conditions for DIV survival. Math Biosci 125, 127–153.[CrossRef]
    [Google Scholar]
  44. Nowak, M. A. & Bangham, C. R. ( 1996; ). Population dynamics of immune responses to persistent viruses. Science 272, 74–79.[CrossRef]
    [Google Scholar]
  45. Nowak, M. A. & May, R. M. ( 2000; ). Virus Dynamics: Mathematical Principles of Immunology and Virology. Oxford, UK. : Oxford University Press.
    [Google Scholar]
  46. Nowak, M. A., May, R. M. & Anderson, R. M. ( 1990; ). The evolutionary dynamics of HIV-1 quasispecies and the development of immunodeficiency disease. AIDS 4, 1095–1103.[CrossRef]
    [Google Scholar]
  47. Ogg, G. S., Kostense, S., Klein, M. R., Jurriaans, S., Hamann, D., McMichael, A. J. & Miedema, F. ( 1999; ). Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression. J Virol 73, 9153–9160.
    [Google Scholar]
  48. Okuma, K., Boritz, E., Walker, J., Sarkar, A., Alexander, L. & Rose, J. K. ( 2006; ). Recombinant vesicular stomatitis viruses encoding simian immunodeficiency virus receptors target infected cells and control infection. Virology 346, 86–97.[CrossRef]
    [Google Scholar]
  49. Payne, R. J. & Jansen, V. A. ( 2003; ). Pharmacokinetic principles of bacteriophage therapy. Clin Pharmacokinet 42, 315–325.[CrossRef]
    [Google Scholar]
  50. Perelson, A. S. & Nelson, P. ( 1999; ). Mathematical analysis of HIV-1 in vivo. SIAM Rev 41, 3–44.[CrossRef]
    [Google Scholar]
  51. Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, J. M. & Ho, D. D. ( 1996; ). HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582–1586.[CrossRef]
    [Google Scholar]
  52. Perelson, A. S., Essunger, P., Cao, Y., Vesanen, M., Hurley, A., Saksela, K., Markowitz, M. & Ho, D. D. ( 1997; ). Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188–191.[CrossRef]
    [Google Scholar]
  53. Phillips, A. N. ( 1996; ). Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271, 497–499.[CrossRef]
    [Google Scholar]
  54. Pierson, T., McArthur, J. & Siliciano, R. F. ( 2000; ). Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 18, 665–708.[CrossRef]
    [Google Scholar]
  55. Ramratnam, B., Bonhoeffer, S., Binley, J., Hurley, A., Zhang, L., Mittler, J. E., Markowitz, M., Moore, J. P., Perelson, A. S. & Ho, D. D. ( 1999; ). Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354, 1782–1785.[CrossRef]
    [Google Scholar]
  56. Revilla, T. & García-Ramos, G. ( 2003; ). Fighting a virus with a virus: a dynamic model for HIV-1 therapy. Math Biosci 185, 191–203.[CrossRef]
    [Google Scholar]
  57. Ribeiro, R. M., Mohri, H., Ho, D. D. & Perelson, A. S. ( 2002; ). In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted? Proc Natl Acad Sci U S A 99, 15572–15577.[CrossRef]
    [Google Scholar]
  58. Richman, D. D. ( 2000; ). Normal physiology and HIV pathophysiology of human T-cell dynamics. J Clin Invest 105, 565–566.[CrossRef]
    [Google Scholar]
  59. Rose, J. K. & Whitt, M. A. ( 2001; ). Rhabdoviridae: The Viruses and Their Replication, 4th edn. New York. : Lippincott Williams & Wilkins.
    [Google Scholar]
  60. Schnell, M. J., Johnson, J. E., Buonocore, L. & Rose, J. K. ( 1997; ). Construction of a novel virus that targets HIV-1-infected cells and controls HIV-1 infection. Cell 90, 849–857.[CrossRef]
    [Google Scholar]
  61. Stafford, M. A., Corey, L., Cao, Y., Daar, E. S., Ho, D. D. & Perelson, A. S. ( 2000; ). Modeling plasma virus concentration during primary HIV infection. J Theor Biol 203, 285–301.[CrossRef]
    [Google Scholar]
  62. Stilianakis, N. I. & Schenzle, D. ( 2006; ). On the intra-host dynamics of HIV-1 infections. Math Biosci 199, 1–25.[CrossRef]
    [Google Scholar]
  63. 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]
  64. Vrisekoop, N., van Gent, R., de Boer, A. B., Otto, S. A., Borleffs, J. C. C., Steingrover, R., Prins, J. M., Kuijpers, T. W., Wolfs, T. F. W. & other authors ( 2008; ). Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging. J Immunol 181, 1573–1581.[CrossRef]
    [Google Scholar]
  65. Weinberger, L. S., Schaffer, D. V. & Arkin, A. P. ( 2003; ). Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection. J Virol 77, 10028–10036.[CrossRef]
    [Google Scholar]
  66. Westerhout, E. M., Vink, M., Haasnoot, P. C. J., Das, A. T. & Berkhout, B. ( 2006; ). A conditionally replicating HIV-based vector that stably expresses an antiviral shRNA against HIV-1 replication. Mol Ther 14, 268–275.[CrossRef]
    [Google Scholar]
  67. Wodarz, D. & Jansen, V. A. ( 2001; ). The role of T cell help for anti-viral CTL responses. J Theor Biol 211, 419–432.[CrossRef]
    [Google Scholar]
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