Anti–PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers
Karsten Eichholz, … , Afam A. Okoye, Lawrence Corey
Karsten Eichholz, … , Afam A. Okoye, Lawrence Corey
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e169309. https://doi.org/10.1172/JCI169309.
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Anti–PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers

Abstract

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.

Authors

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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Figure 2

Anti–PD-1 CAR T cells attenuate SIV infection in vitro.

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Anti–PD-1 CAR T cells attenuate SIV infection in vitro. Schematic of the...
Schematic of the production of the infection of CD8-depleted PBMCs with SIVmac239 NefIRESGFP (A). PD-1 expression on infected and noninfected cells after 4 days of infection (n = 3). Shown are fluorescence minus one (FMO) controls for PD-1 and full staining samples (B). Anti–PD-1 CAR T cells prevent viral outgrowth. Schematic showing the time line of preparation of effector cells and autologous CD4+ T cells as target cells infected with SIVmac239 NefIRESGFP directly before the experiment. Cytotoxicity was measured by reduction of GFP+ cells using the IncuCyte Live Cell Imaging System. Representative images at the end of the 96 hours of coculture with effector cells at the indicated E:T ratio (n = 3) (C). Original magnification, ×10. Quantification of GFP+ cells in the images acquired over 96 hours in the killing assay described in C (D). Average cytotoxicity ± SEM of 1 representative experiment is shown. Statistics were analyzed using 2-way ANOVA with Tukey’s multiple-comparisons test at each time point. Results for 72 hours are reported. ****P < 0.0001.