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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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Research Article AIDS/HIV Article has an altmetric score of 10

Anti–PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers

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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 6

Effects of anti–PD-1 CAR T cells in SIV-infected RMs.

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Effects of anti–PD-1 CAR T cells in SIV-infected RMs.
At steady state, T...
At steady state, TFH cells are localized in B cell follicles, where they support B cell responses. Extrafollicular PD-1–expressing T cells are part of the memory compartment or have been recently exposed to antigen. During lentiviral infection, there is an increase of TFH cells, extrafollicular PD-1+ CD4+ and CD8+ T cells, and viral replication occurring predominantly in TFH cells. During successful expansion, anti–PD-1 CAR T cells enter lymphoid tissues and kill extrafollicular PD-1+ T cells as well as TFH cells in the follicles. This results in relatively lower viral replication in the follicles due to depletion of TFH cells and increases viral replication in the extrafollicular T cell zone where it occurs in PD-1 CD4+ T cells. SIV-specific T cells are likely part of the extrafollicular PD-1+ T cell population and are lost due to depletion of anti–PD-1 CAR T cells. Over time, this leads to anti–PD-1 CAR T cell–mediated immunodeficiency.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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