Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy
Benjamin D. Varco-Merth, … , Timothy J. Henrich, Afam A. Okoye
Benjamin D. Varco-Merth, … , Timothy J. Henrich, Afam A. Okoye
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(10):e156063. https://doi.org/10.1172/JCI156063.
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Research Article AIDS/HIV

Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus–infected rhesus macaques on antiretroviral therapy

Abstract

Proliferation of latently infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4+ memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA–treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4+ TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.

Authors

Benjamin D. Varco-Merth, William Brantley, Alejandra Marenco, Derick D. Duell, Devin N. Fachko, Brian Richardson, Kathleen Busman-Sahay, Danica Shao, Walter Flores, Kathleen Engelman, Yoshinori Fukazawa, Scott W. Wong, Rebecca L. Skalsky, Jeremy Smedley, Michael K. Axthelm, Jeffrey D. Lifson, Jacob D. Estes, Paul T. Edlefsen, Louis J. Picker, Cheryl M.A. Cameron, Timothy J. Henrich, Afam A. Okoye

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Figure 1

Plasma and cell-associated viral loads were equivalent between study groups prior to rapamycin treatment.

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Plasma and cell-associated viral loads were equivalent between study gro...
(A) Schematic representation of the study protocol showing SIVmac239M infection, ART initiation 12 days dpi, rapamycin or vehicle control administration, which occurred daily from 231 to 543 dpi, and anti-CD3LALA infusion in rapamycin-treated RMs on 467 and 497 dpi. (B) Mean (+SEM) pvl profiles of rapamycin (red) or vehicle controls (blue) (n = 7 each) prior to treatment initiation. (C) Comparison of SIV RNA and DNA levels in PBMCs and LNs (copies per 106 cell equivalents) between rapamycin (red) and vehicle controls (blue) at 3 days (15 dpi) and 210 days after ART. (D) Quantification of rapamycin drug levels in plasma. (E) Mean (+SEM) change from baseline cholesterol levels in plasma of rapamycin-treated RMs (red) and vehicle controls. (F) Quantification of the number of Glut1+ T cells per 105 cells in LNs at –21, 49, and 91 days after initiation of rapamycin or vehicle in the treatment groups. Each data point represents the average number of Glut1+CD3+ T cells derived from quantitative measures from 2 to 3 LN sections from a single time point from an individual RM. The WRS test was used to determine the significance of differences between the rapamycin or vehicle control treatment groups (P values ≤ 0.05 are shown). Box plots show jittered points, a box from 1st to 3rd quartiles (IQR), and a line at the median, with whiskers extending to the farthest data point within 1.5× IQR above and below the box.