The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy
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
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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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 4

Inducibility of the latent reservoir in PWH on short- and long-term ART.

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Inducibility of the latent reservoir in PWH on short- and long-term ART....
(A) QVOA/IPDA analysis of inducibility. Inducibility was measured as the ratio of the frequency of inducible, replication-competent proviruses per 106 resting CD4+ T cells over the frequency of intact proviruses per 106 resting CD4+ T cells in the same sample (QVOA/IPDA). Short-term ART data are from a study by Bruner et al. (34). The mean duration of treatment with suppressive ART at the time of sampling is shown for each group on the x axis. The geometric mean values (thick line) and statistical significance (Student’s t test on log-transformed values) are indicated. This analysis was performed using data from samples for which both assays were positive. (B) Data from A together with results from samples for which one of the frequencies was below the limit of detection (BLD). For these samples, frequencies were estimated as described in the legend to Figure 2.