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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).
Wong, J.K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291– 1295 (1997).
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).
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).
Chun, T-W. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183 –188 (1997).
Ho, D.D. Toward HIV eradication or remission: the tasks ahead. Science 280, 1866–1867 (1998).
Zhang, L. et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med. 340, 1605–1613 (1999).
Michie, C.A., McLean, A., Alcock, B. & Beverley, P.C. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).
Hellerstein, M. et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nature Med. 5, 83–89 (1999).
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).
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).
Macken, C.A. Design and analysis of serial limiting dilution assays with small sample sizes . J. Immunol. Meth. 222, 13– 29 (1999).
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).
Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection . Nature 373, 117–122 (1995).
Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123– 126 (1995).
Perelson, A.S. et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature 387, 188– 191 (1997).
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).
Natarajan, V. et al. HIV-1 replication in patients with undetectable plasma virus receiving HAART. Lancet 353, 119– 120 (1999).
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).
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).
Altice, F.L. & Friedland, G.H. The era of adherence to HIV therapy. Ann. Intern. Med. 129, 503– 505 (1998).
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).
Palella, F.J. et al. Declining morbidity and mortality among patients with advanced human immunodeficiency. N. Engl. J. Med. 338, 853–860 (1998).
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).
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).
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.
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
Despite early antiretroviral therapy effector memory and follicular helper CD4 T cells are major reservoirs in visceral lymphoid tissues of SIV-infected macaques
Mucosal Immunology (2020)
Relationships Between HIV-Mediated Chemokine Coreceptor Signaling, Cofilin Hyperactivation, Viral Tropism Switch and HIV-Mediated CD4 Depletion
Current HIV Research (2020)
Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion
Nature Communications (2019)
Journal of Virology (2019)
Persistent Viral Reservoirs in Lymphoid Tissues in SIV-Infected Rhesus Macaques of Chinese-Origin on Suppressive Antiretroviral Therapy