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 (mAb) 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 RM during ART. Upon ART cessation, both CD8+ T cell-depleted and control RMs rebounded in <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 ~2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent anti-viral 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.
Okoye AA, Duell DD, Fukazawa Y, Varco-Merth B, Marenco A, Behrens H, Chaunzwa TM, Selseth AN, Gilbride RM, Shao J, Edlefsen PT, Geleziunas R, Pinkevych M, Davenport MP, Busman-Sahay K, Nekorchuk MD, Park H, Smedley JV, Axthelm MK, Estes JD, Hansen SG, Keele BF, Lifson JD, Picker LJ. (2021). CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification. The Journal of clinical investigation