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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-04, Vol.134 (7), p.1-14
Main Authors: Eichholz, Karsten, Fukazawa, Yoshinori, Peterson, Christopher W, Haeseleer, Francoise, Medina, Manuel, Hoffmeister, Shelby, Duell, Derick M, Varco-Merth, Benjamin D, Dross, Sandra, Park, Haesun, Labriola, Caralyn S, Axthelm, Michael K, Murnane, Robert D, Smedley, Jeremy V, Jin, Lei, Gong, Jiaxin, Rust, Blake J, Fuller, Deborah H, Kiem, Hans-Peter, Picker, Louis J, Okoye, Afam A, Corey, Lawrence
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Language:English
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI169309