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:

The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy

Nature Medicine volume 6, pages 82–85 (2000)Cite this article

Abstract

Replication-competent HIV-1 can be isolated from infected patients despite prolonged plasma virus suppression by anti-retroviral treatment1,2,3. Recent studies have identified resting, memory CD4+ T lymphocytes as a long-lived latent reservoir of HIV-1 (refs. 4,5). Cross-sectional analyses indicate that the reservoir is rather small, between 103 and 107 cells per patient5,6. In individuals whose plasma viremia levels are well suppressed by anti-retroviral therapy, peripheral blood mononuclear cells containing replication-competent HIV-1 were found to decay with a mean half-life of approximately 6 months7, close to the decay characteristics of memory lymphocytes in humans and monkeys8,9,10. In contrast, little decay was found in a less-selective patient population11. We undertook this study to address this apparent discrepancy. Using a quantitative micro-culture assay, we demonstrate here that the latent reservoir decays with a mean half-life of 6.3 months in patients who consistently maintain plasma HIV-1 RNA levels of fewer than 50 copies/ml. Slower decay rates occur in individuals who experience intermittent episodes of plasma viremia. Our findings indicate that the persistence of the latent reservoir of HIV-1 despite prolonged treatment is due not only to its slow intrinsic decay characteristics but also to the inability of current drug regimens to completely block HIV-1 replication.

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: Changes in plasma HIV-1 RNA and titer of replication-competent virus (IUPM) during treatment.
Figure 2: Correlation between the decay slope of the latent reservoir and episodes of intermittent viremia.

Similar content being viewed by others

References

  1. 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 

  2. 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 

  3. 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 

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

    Article  CAS  Google Scholar 

  5. 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 

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

    Article  CAS  Google Scholar 

  7. 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 

  8. Michie, C.A., McLean, A., Alcock, B. & Beverley, P.C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).

    Article  CAS  Google Scholar 

  9. Hellerstein, M. et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nature Med. 5, 83–89 (1999).

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

  12. Macken, C.A. Design and analysis of serial limiting dilution assays with small sample sizes . J. Immunol. Meth. 222, 13– 29 (1999).

    Article  CAS  Google Scholar 

  13. 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 

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

    Article  CAS  Google Scholar 

  15. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gunthard, H.F. et al. Higher selection pressure from antiretroviral drugs in vivo results in increased evolutionary distance in HIV-1 pol. Virology 259, 154–165 ( 1999).

    Article  CAS  Google Scholar 

  21. Altice, F.L. & Friedland, G.H. The era of adherence to HIV therapy. Ann. Intern. Med. 129, 503– 505 (1998).

    Article  CAS  Google Scholar 

  22. Lucas, G.M., Chaisson, R.E. & Moore, R.D. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann. Intern. Med. 131, 81–87 (1999).

    Article  CAS  Google Scholar 

  23. Palella, F.J. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency. N. Engl. J. Med. 338, 853–860 (1998).

    Article  Google Scholar 

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

    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 anti-retroviral therapy. Nature Med. 5, 651–655 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Krikoun for technical assistance, E. Jones for help with data collection and W. Chen for preparation of the figures. This work was supported by National Institutes of Health grants AI40387, RR06555 and AI41534, the Columbia–Rockefeller Center for AIDS Reseach (AI42848), the General Clinical Research Center of The Rockefeller University (MO1-RR00102), The Belotsky Foundation, The Irene Diamond Fund and the Bristol Myers Squibb Foundation. B.R. is supported by the Rockefeller University Clinical Scholar's Program.

Author information

Authors and Affiliations

  1. Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York, 10016, New York, USA

    Bharat Ramratnam, Linqi Zhang, Daniel Boden, Arlene Hurley, Fang Fang, Martin Markowitz & David D. Ho

  2. Los Alamos National Laboratory, Los Alamos, 87545, New Mexico, USA

    John E. Mittler, Catherine A. Macken & Alan S. Perelson

Authors
  1. Bharat Ramratnam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John E. Mittler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linqi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Boden
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arlene Hurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Catherine A. Macken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alan S. Perelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Martin Markowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David D. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David D. Ho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ramratnam, B., Mittler, J., Zhang, L. et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med 6, 82–85 (2000). https://doi.org/10.1038/71577

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/71577

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