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

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.

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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.

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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.

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Correspondence to David D. Ho.

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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

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