Abstract
Human immunodeficiency virus type 1 (HIV-1) infects cells of the immune system and leads to depletion of CD4+ T cells, and to an increase of CD8+ T-lymphocytes. However, not much is known about the dynamics of turnover (proliferation and death) of the CD4+ and CD8+ T cell populations in HIV-infected and healthy individuals. A new experimental technique has been developed using deuterated-glucose labeling that provides information on cell turnover in vivo. However, the quantitative interpretation of the data requires the development of specific dynamic models. In this paper we derive two models, a simple one-compartment model and a more complex two-compartment model. These models allow for robust quantification of death and proliferation rates, but careful consideration of the system is necessary to understand what is being measured in each case. We demonstrate that more realistic models can account not only for differences in the turnover rates between HIV-infected and healthy individuals, but also take into consideration the elevated state of activation in HIV infection. The use of these models in the interpretation of the experimental data will increase our knowledge of T cell dynamics in the context of HIV infection.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bonhoeffer, S., H. Mohri, D. Ho and A. S. Perelson (2000). Quantification of cell turnover kinetics using 5-bromo-2′-deoxyuridine. J. Immunol. 164, 5049–5054.
Cavert, W. et al. (1997). Kinetics of response in lymphoid tissues to antiretroviral theraoy of HIV-1 infection. Science 276, 960–964.
Clark, D. R., R. J. DeBoer, K. C. Wolthers and F. Miedema (1999). T cell dynamics in HIV-1 infection. Adv. Immunol. 73, 301–327.
Cleaver, J. E. (1967). Thymidine Metabolism and Cell Kinetics, Amsterdam: North Holland.
Efron, B. and R. Tibshirani (1986). Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy. Stat. Sci. 1, 54–77.
Fleury, S. et al. (2000). Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA 97, 5393–5398.
Grossman, Z., R. B. Herberman and D. S. Dimitrov (1999). T cell turnover in SIV infection. Science 284, 555a.
Haase, A. T. et al. (1996). Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989.
Hazenberg, M. D., D. Hamann, H. Schuitemaker and F. Miedema (2000a). T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat. Immunol. 1, 285–289.
Hazenberg, M. D., J. W. Stuart, S. A. Otto, J. C. Borleffs, C. A. Boucher, R. J. DeBoer, F. Miedema and D. Hamann (2000b). 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.
Hellerstein, M. et al. (1999). Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat. Med. 5, 83–89.
Hellerstein, M. K. (1999). Measurement of T-cell kinetics: recent methodologic advances. Immunol. Today 20, 438–441.
Lempicki, R. A. et al. (2000). Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc. Natl. Acad. Sci. USA 97, 13778–13783.
Macallan, D. C., C. A. Fullerton, R. A. Neese, K. Haddock, S. S. Park and M. K. Hellerstein (1998). Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans. Proc. Natl. Acad. Sci. USA 95, 708–713.
Mackall, C. L. et al. (1995). Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. New Engl. J. Med. 332, 143–149.
McCune, J. M. (2001). The dynamics of CD4+ T cell depletion in HIV disease. Nature 410, 974–979.
McCune, J. M. et al. (2000). Factors influencing T-cell turnover in HIV-1-seropositive patients. J. Clin. Invest. 105, R1–R8.
McLean, A. R. and C. Michie (1995). In vivo estimates of division and death rates of human T lymphocytes. Proc. Natl. Acad. Sci. USA 92, 3707–3711.
Mohri, H., S. Bonhoeffer, S. Monard, A. S. Perelson and D. D. Ho (1998). Rapid turnover of T lymphocytes in SIV infected rhesus macaques. Science 279, 1223–1227.
Mohri, H. et al. (2001). Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J. Exp. Med. 194, 1277–1287.
Pantaleo, G. (1999). Unraveling the strands of HIV’s web. Nat. Med. 5, 27–28.
Pantaleo, G. and A. S. Fauci (1996). Immunopathogenesis of HIV infection. Annu. Rev. Microbiol. 50, 825–854.
Ribeiro, R. M., H. Mohri, D. D. Ho and A. S. Perelson (2002). In preparation.
Wong, J. K., H. F. Gunthard, D. V. Havlir, Z. Q. Zhang, A. T. Haase, C. C. Igancio, S. Kwok, E. Emini and D. D. Richman (1997). Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure. Proc. Natl. Acad. Sci. USA 94, 12574–12579.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ribeiro, R.M., Mohri, H., Ho, D.D. et al. Modeling deuterated glucose labeling of T-lymphocytes. Bull. Math. Biol. 64, 385–405 (2002). https://doi.org/10.1006/bulm.2001.0282
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1006/bulm.2001.0282