Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy

Nature Medicine volume 6, pages 757–761 (2000)Cite this article

Abstract

We examined the pathogenic significance of the latent viral reservoir in the resting CD4+ T cell compartment of HIV-1-infected individuals as well as its involvement in the rebound of plasma viremia after discontinuation of highly active anti-retroviral therapy (HAART). Using heteroduplex mobility and tracking assays, we show that the detectable pool of latently infected, resting CD4+ T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. In the majority of patients examined, the rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and the replication-competent virus within the detectable pool of latently infected, resting CD4+ T cells. These results indicate the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia after cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Re-emergence of plasma viremia and the size of the pool of latently infected, resting CD4+ T cells in infected patients before and after discontinuation of HAART.
Figure 2: Heteroduplex mobility and tracking analysis of rebounding plasma HIV after discontinuation of HAART using cell-associated HIV RNA from the latent reservoir as probes for patients in whom no culturable replication-competent virus was detected.
Figure 3: Heteroduplex tracking analysis of rebounding plasma HIV after discontinuation of HAART using cell-associated HIV RNA from the latent reservoir as probes for patients in whom infectious virus was recovered at baseline.
Figure 4: Heteroduplex tracking analysis of replication-competent HIV derived from resting CD4+ T cells over time in co-cultures.
Figure 5: Heteroduplex tracking analysis of rebounding plasma HIV after discontinuation of HAART using co-cultured, replication-competent HIV RNA from the latent reservoir as probes.

Similar content being viewed by others

References

  1. Gulick, R.M. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior anti-retroviral therapy . N. Engl. J. Med. 337, 734– 739 (1997).

    Article  CAS  Google Scholar 

  2. Hammer, S.M. et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N. Engl. J. Med. 337, 725– 733 (1997).

    Article  CAS  Google Scholar 

  3. Palella, F.J. Jr. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 338, 853–860 (1998).

    Article  Google Scholar 

  4. Detels, R. et al. Effectiveness of potent anti-retroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA 280, 1497– 1503 (1998).

    Article  CAS  Google Scholar 

  5. Hoyert, D.L., Kochanek, K.D. & Murphy, S.L. Deaths: final data for 1997. Natl. Vital Stat. Rep. 47, 1–104 ( 1999).

    PubMed  Google Scholar 

  6. Mocroft, A. et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352, 1725–1730 (1998).

    Article  CAS  Google Scholar 

  7. Dore, G.J., Brown, T., Tarantola, D. & Kaldor, J.M. HIV and AIDS in the Asia-Pacific region: an epidemiological overview. Aids 12 Suppl B, S1–10 ( 1998).

    PubMed  Google Scholar 

  8. Perelson, A.S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188– 191 (1997).

    Article  CAS  Google Scholar 

  9. Natarajan, V. et al. HIV-1 replication in patients with undetectable plasma virus receiving HAART. Lancet 353, 119– 120 (1999).

    Article  CAS  Google Scholar 

  10. Furtado, M.R. et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent anti-retroviral therapy. N. Engl. J. Med. 340, 1614–1622 (1999).

    Article  CAS  Google Scholar 

  11. Lewin, S.R. et al. Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J. Virol. 73, 6099–6103 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Gunthard, H.F. et al. Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy . J. Virol. 73, 9404–9412 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Wong, J.K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291– 1295 (1997).

    Article  CAS  Google Scholar 

  16. Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med. 5, 512–517 ( 1999).

    Article  CAS  Google Scholar 

  17. Zhang, L. et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med. 340, 1605–1613 (1999).

    Article  CAS  Google Scholar 

  18. Chun, T.W. et al. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nature Med. 1, 1284–1290 (1995).

    Article  CAS  Google Scholar 

  19. Chun, T.W. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 (1997).

    Article  CAS  Google Scholar 

  20. Chun, T.W. et al. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc. Natl. Acad. Sci. USA 95, 8869–8873 ( 1998).

    Article  CAS  Google Scholar 

  21. Chun, T.W., Engel, D., Mizell, S.B., Ehler, L.A. & Fauci, A.S. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J. Exp. Med. 188, 83–91 (1998).

    Article  CAS  Google Scholar 

  22. Ho, D.D. Toward HIV eradication or remission: the tasks ahead. Science 280, 1866–1867 (1998).

    Article  CAS  Google Scholar 

  23. Schrager, L.K. & D'Souza, M.P. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 280, 67– 71 (1998).

    Article  CAS  Google Scholar 

  24. Cohen, J. Exploring how to get at—and eradicate—hidden HIV. Science 279, 1854–1855 ( 1998).

    Article  CAS  Google Scholar 

  25. Chun, T.W. et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active antiretroviral therapy. Nature Med. 5, 651– 655 (1999).

    Article  CAS  Google Scholar 

  26. Chun, T.-W., Davey, R.T., Engel, D., Lane, H.C. & Fauci, A.S. Re-emergence of HIV after stopping therapy. Nature 401, 874–875 ( 1999).

    Article  CAS  Google Scholar 

  27. Davey, R.T., Jr. et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl. Acad. Sci. U S A 96, 15109–15114 (1999).

    Article  CAS  Google Scholar 

  28. Delwart, EL. et al. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes. Science 262, 1257–1261 (1993).

    Article  CAS  Google Scholar 

  29. Delwart, E.L. & Gordon, C J. Tracking changes in HIV-1 envelope quasispecies using DNA heteroduplex analysis. Methods 12, 348–354 (1997).

    Article  CAS  Google Scholar 

  30. Delwart, E.C., Herring, A., Rodrigo, A.G. & Mullins, J.I. Genetic subtyping of human immunodeficiency virus using a heteroduplex mobility assay. PCR Methods and Applications. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 4, S202– S216 (1995).

    Article  CAS  Google Scholar 

  31. Wolinsky, S.M. et al. Selective transmission of human immunodeficiency virus type-1 variants from mothers to infants. Science 255, 1134–1137 (1992).

    Article  CAS  Google Scholar 

  32. Zhu, T. et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261, 1179– 1181 (1993).

    Article  CAS  Google Scholar 

  33. Zhang, L.Q. et al. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J. Virol. 67, 3345–3356 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Delwart, E.L., Sheppard, H.W., Walker, B.D., Goudsmit, J. & Mullins, J.I. Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays. J. Virol.. 68, 6672–6683 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wolinsky, S.M. et al. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272 , 537–542 (1996).

    Article  CAS  Google Scholar 

  36. Lukashov, V.V. & Goudsmit, J. HIV heterogeneity and disease progression in AIDS: a model of continuous virus adaptation. Aids 12 Suppl A, S43–52 (1998).

    PubMed  Google Scholar 

  37. Cohen, O.J. & Fauci, A.S. HIV/AIDS in 1998-gaining the upper hand? JAMA 280, 87–88 (1998).

    Article  CAS  Google Scholar 

  38. Chun, T.W. & Fauci, A.S. Latent reservoirs of HIV: Obstacles to the eradication of virus. Proc. Natl. Acad. Sci. USA 96, 10958–10961 (1999).

    Article  CAS  Google Scholar 

  39. Cavert, W. et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960–964 (1997).

    Article  CAS  Google Scholar 

  40. Cavert, W. & Haase, A.T. A national tissue bank to track HIV eradication and immune reconstruction. Science 280, 1865–1866 (1998).

    Article  CAS  Google Scholar 

  41. Zhang, H. et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N. Engl. J. Med. 339, 1803–1809 (1998).

    Article  CAS  Google Scholar 

  42. Ostrowski, M.A. et al. Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies. J. Virol. 72, 7772–7784 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank C. Yoder and J. Metcalf for scheduling patient visits and for providing patient laboratory data. They also thank S. Moir for helpful discussions and review of the manuscript and the National Institute of Allergy and Infectious Disease Study Coordinators and Case Managers as well as their patients for their willingness to participate in these studies.

Author information

Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health,, 20892, Bethesda, Maryland

    Tae-Wook Chun, Richard T. Davey Jr., Mario Ostrowski, J. Shawn Justement, Delphine Engel & Anthony S. Fauci

  2. Department of Microbiology, University of Washington, Seattle, 98104, Washington

    James I. Mullins

Authors
  1. Tae-Wook Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard T. Davey Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario Ostrowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Shawn Justement
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Delphine Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James I. Mullins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony S. Fauci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae-Wook Chun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chun, TW., Davey, R., Ostrowski, M. et al. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy . Nat Med 6, 757–761 (2000). https://doi.org/10.1038/77481

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/77481

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing