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 3

Equivalence of SIV-specific T cell response development between study groups prior to mAb treatment.

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Equivalence of SIV-specific T cell response development between study gr...
(A and B) Mean (+SEM) frequencies of CD4+ and CD8+ memory T cells (Tm) in peripheral blood and lung airspace (obtained by bronchoalveolar lavage) specific for SIV Gag, Rev/Tat/Nef, Env, and Pol following SIVmac239M infection and ART initiation at 12 days pi in RMs selected for the anti-CD8β treatment group (red; n = 10) versus the IgG isotype control group (blue; n = 10). These response frequencies were determined by intracellular expression of TNF-α and/or IFN-γ after stimulation with mixes of consecutive, overlapping 15-mer peptides for each SIV protein (Gag, Env, Pol) or protein combination (Rev/Tat/Nef) with the total response to these SIV proteins, reflecting the sum of the Gag + Rev/Tat/Nef + Env + Pol responses, shown. (C and D) Mean (+SEM) frequencies of peripheral blood CD8+ Tm specific for SIV Gag CM9, Tat SL8, Nef RL10, and Vif RL9 determined by tetramer staining for each SIV epitope as described in the Methods section. In A–D, Wilcoxon’s rank-sum test was used to determine the significance of differences between the treatment groups (unadjusted P values shown).