The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy
Natalie F. McMyn, … , Robert F. Siliciano, Janet M. Siliciano
Natalie F. McMyn, … , Robert F. Siliciano, Janet M. Siliciano
Published July 18, 2023
Citation Information: J Clin Invest. 2023;133(17):e171554. https://doi.org/10.1172/JCI171554.
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Research Article AIDS/HIV Virology Article has an altmetric score of 12

The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy

Abstract

HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.

Authors

Natalie F. McMyn, Joseph Varriale, Emily J. Fray, Carolin Zitzmann, Hannah MacLeod, Jun Lai, Anushka Singhal, Milica Moskovljevic, Mauro A. Garcia, Brianna M. Lopez, Vivek Hariharan, Kyle Rhodehouse, Kenneth Lynn, Pablo Tebas, Karam Mounzer, Luis J. Montaner, Erika Benko, Colin Kovacs, Rebecca Hoh, Francesco R. Simonetti, Gregory M. Laird, Steven G. Deeks, Ruy M. Ribeiro, Alan S. Perelson, Robert F. Siliciano, Janet M. Siliciano

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Figure 3

Decay of the latent reservoir during very long-term ART.

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Decay of the latent reservoir during very long-term ART. (A) QVOA measur...
(A) QVOA measurements of the frequencies of resting CD4+ T cells with inducible, replication-competent proviruses in 4 PWH from the original 2003 study (29) who were sampled again after a total of 15–27 years on suppressive ART. Frequencies for the first 7 years of ART from other participants in Siliciano et al. (29) are shown by red circles. For assays with no outgrowth, the median posterior estimate of infected-cell frequency based on input cell number was plotted (open symbols). Monophasic decay with t1/2 = 44 months is indicated by the dashed red line. (B) QVOA measurements for all participants in the current study. Lines connect longitudinal measurements in the same donor. A best fit model for segmented exponential decay (thick gray line) shows initial decay with t1/2 = 44 months followed by an inflection at 7 years and then a slow increase (doubling time = 23 years). See Supplemental Table 5 for details. (C) IPDA measurements of the decay of intact proviruses in PWH on very long-term ART. Frequencies for the initial years of ART (red circles) were replotted from Peluso et al. (35). Results are expressed as the DNA shearing index–corrected (DSI-corrected) geometric mean frequency of intact proviruses in resting CD4+ T cells (34). For assays in which no intact proviruses were detected, results are reported as the inverse of the number of cell equivalents analyzed (open symbols). The DSI was below 0.5 for all participants. Monophasic decay with a half-life of 44.2 months is indicated by the dashed line. A model for segmented exponential decay (thick gray line) shows initial decay with t1/2 = 46 months followed by an inflection at 7 years and slower subsequent decay (t1/2 = 9 years). See Supplemental Table 6 for details.