BACKGROUND: Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently-infected CD4+ T cells containing replication-competent human immune deficiency virus 1 (HIV) provirus in people with HIV on antiretroviral therapy (ART).
METHODS: We engineered novel chimeric antigen receptor (CAR) T cells that can efficiently kill PD-1 expressing cells in vitro and in vivo to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in simian immunodeficiency virus (SIV) mac239-infected rhesus macaques (RMs). Adoptive transfer experiments of anti-PD-1 CAR T cells were done in 2 SIV naïve and 4 SIV-infected RMs on ART.
RESULTS: In 3 of 6 RMs, one SIV naïve and 2 SIV+ RMs, anti-PD-1 CAR T cells expanded efficiently and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including CD4+ follicular helper T cells (T_FH). This depletion of T_FH in lymph nodes was also associated with depletion of detectable SIV RNA from the germinal center (GC). However, following 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 acute depletion of CD8+ memory T cells after CAR T infusion in SIV+ RMs on ART.
CONCLUSIONS: These data indicate anti-PD-1 CAR T cells can target and deplete PD-1+ T cells in vivo including GC T_FH cells and eradicate SIV from this immunological sanctuary. Approaches to limit CAR T cell-mediated depletion to PD-1+ CD4+ T cell reservoirs and reduced off target CD8+ memory T cell depletion should be pursued.