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HIV preferentially infects HIV-specific CD4+ T cells

Abstract

HIV infection is associated with the progressive loss of CD4+ T cells through their destruction or decreased production1,2. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4+ T cells are preferentially affected3,4,5. Here we show that HIV-specific memory CD4+ T cells in infected individuals contain more HIV viral DNA than other memory CD4+ T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4+ T cells increases to a greater extent than in memory CD4+ T cells of other specificities. These findings show that HIV-specific CD4+ T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4+ T-cell responses, and consequently the loss of immunological control of HIV replication6. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.

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Figure 1: HIV viral DNA content of memory CD4+ T cells in infected individuals.
Figure 2: Effects of cell division and interferon-γ secretion on HIV infection of CD4+ T cells that had been stimulated by staphylococcal enterotoxin B.
Figure 3: Viral DNA content of memory CD4+ T cells in infected individuals on and off antiretroviral therapy, ART.

References

  1. Rowland-Jones, S. HIV infection: where have all the T cells gone? Lancet 354, 5–7 (1999)

    CAS  Article  PubMed  Google Scholar 

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

    ADS  CAS  Article  PubMed  Google Scholar 

  3. Rosenberg, E. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  4. Rosenberg, E. S. et al. Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 (2000)

    ADS  CAS  Article  PubMed  Google Scholar 

  5. Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382–3387 (2000)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Pitcher, C. J. et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Med. 5, 518–525 (1999)

    CAS  Article  PubMed  Google Scholar 

  7. Betts, M. R. et al. 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 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Eckstein, D. A. et al. HIV-1 actively replicates in naive CD4( + ) T cells residing within human lymphoid tissues. Immunity 15, 671–682 (2001)

    CAS  Article  PubMed  Google Scholar 

  9. Altfeld, M. et al. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J. Exp. Med. 193, 169–180 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Bird, J. J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998)

    CAS  Article  PubMed  Google Scholar 

  11. Kalams, S. A. et al. Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J. Virol. 73, 6715–6720 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wilson, J. D. et al. Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease. J. Infect. Dis. 182, 792–798 (2000)

    CAS  Article  PubMed  Google Scholar 

  13. McNeil, A. C. et al. High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation. Proc. Natl Acad. Sci. USA 98, 13878–13883 (2001)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Pantaleo, G. et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362, 355–358 (1993)

    ADS  CAS  Article  PubMed  Google Scholar 

  15. Haase, A. T. et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985–989 (1996)

    ADS  CAS  Article  PubMed  Google Scholar 

  16. Zhang, Z.-Q. et al. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc. Natl Acad. Sci. USA 95, 1154–1159 (1998)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 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)

    CAS  Article  PubMed  Google Scholar 

  18. Geijtenbeek, T. B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000)

    CAS  Article  PubMed  Google Scholar 

  19. Cheynier, R. et al. Antigenic stimulation by BCG vaccine as an in vivo driving force for SIV replication and dissemination. Nature Med. 4, 421–427 (1998)

    CAS  Article  PubMed  Google Scholar 

  20. 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)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Chun, T., Chadwick, K., Margolick, J. & Siliciano, R. Differential susceptibility of naive and memory CD4+ T cells to the cytopathic effects of infection with human immunodeficiency virus type 1 strain LAI. J. Virol. 71, 4436–4444 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  24. Carcelain, G. et al. Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection. J. Virol. 75, 234–241 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Blancou, P. et al. The infiltration kinetics of simian immunodeficiency virus-specific T cells drawn to sites of high antigenic stimulation determines local in vivo viral escape. Proc. Natl Acad. Sci. USA 98, 13237–13242 (2001)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Lisziewicz, J. et al. Control of HIV despite the discontinuation of antiretroviral therapy. N. Engl. J. Med. 340, 1683–1684 (1999)

    CAS  Article  PubMed  Google Scholar 

  27. Ortiz, G. M. et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J. Clin. Invest. 104, R13–R18 (1999)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Deeks, S. G. et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N. Engl. J. Med. 344, 472–480 (2001)

    CAS  Article  PubMed  Google Scholar 

  29. Altfeld, M. & Walker, B. D. Less is more? STI in acute and chronic HIV-1 infection. Nature Med. 7, 881–884 (2001)

    CAS  Article  PubMed  Google Scholar 

  30. Dybul, M. et al. Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters. Proc. Natl Acad. Sci. USA 98, 15161–15166 (2001)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Waldrop, S. L., Pitcher, C. J., Peterson, D. M., Maino, V. C. & Picker, L. J. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. J. Clin. Invest. 99, 1739–1750 (1997)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Hanon, E. et al. Fratricide among CD8( + ) T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity 13, 657–664 (2000)

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank the patients and staff at UTSW Medical Center and the NIH for their cooperation, and M. Roederer and J. Mascola for their help. This work was supported by the UK Medical Research Council (D.A.P.), the Wellcome Trust, and the National Institutes of Health (S.W.).

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Correspondence to Daniel C. Douek.

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Douek, D., Brenchley, J., Betts, M. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002). https://doi.org/10.1038/417095a

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