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CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause?

Nature Medicine volume 8, pages 319–323 (2002)Cite this article

Is CD4+ cell depletion due to rapid elimination by HIV and failure of the immune system to replace these cells at the required rate? Increasing evidence suggests that this is not the case, and that infection-induced immune activation drives both viral replication and CD4+ cell depletion.

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Figure 1: Regenerative proliferation and transient clonal expansion contribute to T cell turnover.
Figure 2: Progressive depletion of resting T cells is depicted as a shifting steady state.

References

  1. Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).

    Article  CAS  Google Scholar 

  2. Mohri, H., Bonhoeffer, S., Monard, S., Perelson, A.S. & Ho, D.D. Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science 279, 1223–1227 (1998).

    Article  CAS  Google Scholar 

  3. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).

    Article  CAS  Google Scholar 

  4. Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M. & Ho, D.D. HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582–1586 (1996).

    Article  CAS  Google Scholar 

  5. Mohri, H. et al. Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J. Exp. Med. 194, 1277–1287 (2001).

    Article  CAS  Google Scholar 

  6. Kovacs, J.A. et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J. Exp. Med. 194, 1731–1741 (2001).

    Article  CAS  Google Scholar 

  7. Grossman, Z. & Paul, W.E. The impact of HIV on naive T-cell homeostasis. Nature Med. 6, 976–977 (2000).

    Article  CAS  Google Scholar 

  8. Grossman, Z., Herberman, R.B., Dimitrov, D.S. T cell turnover in SIV infection. Science 284, 555a–555b (1999).

    Article  Google Scholar 

  9. Cohen Stuart, J.W. et al. The dominant source of CD4+ and CD8+ T-cell activation in HIV infection is antigenic stimulation. J. Acquir. Immune Defic. Syndr. 25, 203–211 (2000).

    Article  CAS  Google Scholar 

  10. Hellerstein, M.K. et al. Kinetic subpopulations of T cells in humans: Effects of HIV-1 infection. in 9th Conference on Retroviruses and Opportunistic Infections (Seattle, Washington, 2002).

    Google Scholar 

  11. Arron, S.T., Gettie, A., Blanchard, J., Ho, D.D. & Zhang, L. Impact of thymectomy on the peripheral T-cell pool in Rhesus macaques before and after infection with SIV. in 9th Conference on Retroviruses and Opportunistic Infections (Seattle, Washington, 2002).

    Google Scholar 

  12. Deeks, S.G. et al. CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy. J. Infect. Dis. 185, 315–323 (2002).

    Article  CAS  Google Scholar 

  13. Broussard, S.R. et al. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J. Virol. 75, 2262–2275 (2001).

    Article  CAS  Google Scholar 

  14. Kaur, A. et al. Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques. J. Virol. 72, 9597–9611 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Feinberg, M. Nonpathogenic infections in animal models. in 9th Conference on Retroviruses and Opportunistic Infections (Seattle, Washington, 2002).

    Google Scholar 

  16. Grossman, Z., Sousa, A.E., Carneiro, J. & Victorino, R.M.M. CD4+ T-cell depletion is linked more directly to immune activation than to HIV turnover: lessons from HIV2 infection and from discordant responses to therapy. J. Human Virol. 4, 132 (abstract) (2001).

    Google Scholar 

  17. Grossman, Z., Feinberg, M.B. & Paul, W.E. Multiple modes of cellular activation and virus transmission in HIV infection: a role for chronically and latently infected cells in sustaining viral replication. Proc. Natl. Acad. Sci. USA 95, 6314–6319 (1998).

    Article  CAS  Google Scholar 

  18. Grossman, Z., Bentwich, Z. & Herberman, R.B. From HIV infection to AIDS: are the manifestations of effective immune resistance misinterpreted? Clin. Immunol. Immunopathol. 69, 123–135 (1993).

    Article  CAS  Google Scholar 

  19. Veazey, R.S. et al. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo. J. Virol. 74, 57–64 (2000).

    Article  CAS  Google Scholar 

  20. Roederer, M., De Rosa, S.C., Watanabe, N. & Herzenberg, L.A. Dynamics of fine T-cell subsets during HIV disease and after thymic ablation by mediastinal irradiation. Semin. Immunol. 9, 389–396 (1997).

    Article  CAS  Google Scholar 

  21. Lyles, R.H. et al. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J. Infect. Dis. 181, 872–880 (2000).

    Article  CAS  Google Scholar 

  22. Anderson, R.W., Ascher, M.S. & Sheppard, H.W. Direct HIV cytopathicity cannot account for CD4 decline in AIDS in the presence of homeostasis: A worst-case dynamic analysis. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 17, 245–252 (1998).

    Article  CAS  Google Scholar 

  23. Grossman, Z. & Herberman, R.B. T-cell homeostasis in HIV infection is neither failing nor blind: modified cell counts reflect an adaptive response of the host. Nature Med. 3, 486–490 (1997).

    Article  CAS  Google Scholar 

  24. Pantaleo, G. Unraveling the strands of HIV's web. Nature Med. 5, 27–28 (1999).

    Article  CAS  Google Scholar 

  25. Hazenberg, M.D., Hamann, D., Schuitemaker, H. & Miedema, F. T cell depletion in HIV-1 infection: How CD4+ T cells go out of stock. Nature Immunol. 1, 285–289 (2000).

    Article  CAS  Google Scholar 

  26. Hazenberg, M.D. et al. 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 (2000).

    CAS  PubMed  Google Scholar 

  27. Hazenberg, M.D. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nature Med. 6, 1036–1042 (2000).

    Article  CAS  Google Scholar 

  28. McCune, J.M. The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410, 974–979 (2001).

    Article  CAS  Google Scholar 

  29. Lempicki, R.A. et al. 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 (2000).

    Article  CAS  Google Scholar 

  30. Kalinkovich, A. et al. Decreased CD4 and increased CD8 counts with T cell activation is associated with chronic helminth infection. Clin. Exp. Immunol. 114, 414–421 (1998).

    Article  CAS  Google Scholar 

  31. Hayashi, N.L.D., Hu-Li, J., Ben-Sasson, S.Z. & Paul, W.E. Antigen-challenge leads to in-vivo activation and elimination of highly polarized TH1 memory T cells. Proc. Natl. Acad. Sci. USA (in the press).

  32. Douek, D.C. et al. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J. Immunol. 167, 6663–6668 (2001).

    Article  CAS  Google Scholar 

  33. Douek, D.C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).

    Article  CAS  Google Scholar 

  34. Haase, A.T. Population biology of HIV-1 infection: Viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu. Rev. Immunol. 17, 625–656 (1999).

    Article  CAS  Google Scholar 

  35. Clerici, M. et al. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J. Clin. Invest. 84, 1892–1899 (1989).

    Article  CAS  Google Scholar 

  36. Grossman, Z. & Paul, W.E. Autoreactivity, dynamic tuning and selectivity. Curr. Opin. Immunol. 13, 687–698 (2001).

    CAS  Google Scholar 

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Acknowledgements

We thank Angelika Meier-Schellersheim for preparing the figures.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Zvi Grossman

  2. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Zvi Grossman, Martin Meier-Schellersheim & William E. Paul

  3. Institute of Molecular Medicine, Faculty of Medicine of Lisbon, Portugal

    Ana E. Sousa & Rui M.M. Victorino

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Grossman, Z., Meier-Schellersheim, M., Sousa, A. et al. CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause?. Nat Med 8, 319–323 (2002). https://doi.org/10.1038/nm0402-319

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