CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification
Afam A. Okoye, … , Jeffery D. Lifson, Louis J. Picker
Afam A. Okoye, … , Jeffery D. Lifson, Louis J. Picker
Published February 25, 2021
Citation Information: J Clin Invest. 2021;131(8):e141677. https://doi.org/10.1172/JCI141677.
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Research Article AIDS/HIV

CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification

Abstract

To define the contribution of CD8+ T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term CD8+ T cell depletion using a rhesusized anti-CD8β monoclonal antibody on barcoded SIVmac239 dynamics on stable ART and after ART cessation in rhesus macaques (RMs). Among the RMs with full CD8+ T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV RNA+ cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and DNA in blood and tissue relative to control-treated RMs during ART. Upon ART cessation, both CD8+ T cell–depleted and control RMs rebounded in fewer than 12 days, with no difference in the time to viral rebound or in either the number or growth rate of rebounding SIVmac239M barcode clonotypes. However, effectively CD8+ T cell–depleted RMs showed a stable, approximately 2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent antiviral CD8+ T cell responses can develop during ART-suppressed SIV infection, these responses effectively intercept post-ART SIV rebound only after systemic viral replication, too late to limit reactivation frequency or the early spread of reactivating SIV reservoirs.

Authors

Afam A. Okoye, Derick D. Duell, Yoshinori Fukazawa, Benjamin Varco-Merth, Alejandra Marenco, Hannah Behrens, Morgan Chaunzwa, Andrea N. Selseth, Roxanne M. Gilbride, Jason Shao, Paul T. Edlefsen, Romas Geleziunas, Mykola Pinkevych, Miles P. Davenport, Kathleen Busman-Sahay, Michael Nekorchuk, Haesun Park, Jeremy Smedley, Michael K. Axthelm, Jacob D. Estes, Scott G. Hansen, Brandon F. Keele, Jeffery D. Lifson, Louis J. Picker

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Figure 7

Effect of CD8+ T cell depletion on SIV infection dynamics prior to ART withdrawal.

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Effect of CD8+ T cell depletion on SIV infection dynamics prior to ART w...
(A) Individual pvl profiles monitored by a high-sensitivity assay (limit of detection, 1 RNA copy/mL) prior to and during anti-CD8β or IgG isotype control mAb treatment, prior to ART cessation. The area in gray denotes pvl values below threshold of the standard assay (15 RNA copies/mL). There was no significant difference between treatment groups in instance and duration of above–standard threshold pvl as determined by Wilcoxon’s rank-sum and Fisher’s exact tests. (B) Comparison of cell-associated SIV RNA (left panel) and DNA (right panel) levels in PBMCs, LNs, and BM (copies per 1 × 106 cell equivalents) after 9 weeks of treatment with anti-CD8β or IgG control mAb. Each data point represents a single determination from an individual RM. Plots show jittered points with a box from first to third quartiles (IQR) and a line as the median, with whiskers extending to the farthest data point within 1.5 × IQR above and below the box, respectively. (C) Quantification of the number of SIV RNA+ cells per 1 × 105 cells (left panel) and the average number of SIV RNA copies per cell measured in LN tissue sections by RNAscope. In B and C, Wilcoxon’s rank-sum test was used to determine the significance of differences between treatment groups, first excluding RMs with incomplete CD8+ Tm depletion, and then including all treated RMs versus IgG controls (unadjusted P values shown). In all panels, RMs with effective CD8+ T cell depletion (n = 7) are shown in red, RMs with incomplete CD8+ T cell depletion (n = 3) are shown in green, and IgG isotype controls (n = 10) are shown in blue. Closed symbols indicate Mamu-A*01+ RMs and open symbols indicate Mamu-B*08+ RMs.