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

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 2

Reservoir measurements in PWH on long-term ART.

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Reservoir measurements in PWH on long-term ART. (A) QVOA measurements of...
(A) QVOA measurements of inducible, replication-competent proviruses among resting CD4+ T cells of PWH on ART for more than 7 years (mean 20.6 years). Virus was isolated in 54 of 61 assays from 42 participants. For negative assays (open symbols), a posterior median estimate is given (88). Black line, median value; n, number of assays. (B) Violin plots of the frequencies of latently infected cells in positive QVOAs on resting CD4+ T cells from 59 PWH on short-term ART (pink) and 38 PWH on long-term ART (orange). Mean duration of suppressive ART at sampling is on the x axis. Boxes and whiskers indicate middle quartiles and maximum and minimum values, respectively. Red horizontal lines, median; black circles, geometric mean. Expected decay with t1/2 = 44.2 months over the relevant time interval is indicated (dashed line). Short-term ART data are from the 2003 study (29). Short- and long-term frequencies were not statistically different (P = 0.54) by Student’s t test on log-transformed values. (C) Violin plots of the frequencies of intact proviruses as measured in positive IPDAs on samples from 62 PWH on short-term ART (pink) and 34 PWH on long-term ART (orange). Short-term ART data are from ref. 35 using samples obtained between 0.5 and 7 years after ART initiation. Expected decay with t1/2 = 44.2 months over the relevant time interval is indicated (dashed line). Log-transformed values were compared using Student’s t test. (D) IPDA measurements of the frequency of intact and defective proviruses (3′ deleted/hypermutated and 5′ deleted) in resting CD4+ T cells of PWH on suppressive ART for more than 7 years (mean = 22.0 years). Bars indicate median values. For negative assays (open symbols), maximum value based on the number of cells plated is shown. Significance values for multiple comparisons with the log-transformed frequencies of intact proviruses were determined using Dunnett’s test. n, number of assays.