Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti–PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239–infected rhesus macaques (RMs). Adoptive transfer of anti–PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti–PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti–PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.


Karsten Eichholz, Yoshinori Fukazawa, Christopher W. Peterson, Francoise Haeseleer, Manuel Medina, Shelby Hoffmeister, Derick M. Duell, Benjamin D. Varco-Merth, Sandra Dross, Haesun Park, Caralyn S. Labriola, Michael K. Axthelm, Robert D. Murnane, Jeremy V. Smedley, Lei Jin, Jiaxin Gong, Blake J. Rust, Deborah H. Fuller, Hans-Peter Kiem, Louis J. Picker, Afam A. Okoye, Lawrence Corey


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