Targeting PD-1+ T Cells With Chimeric Antigen Receptors to Reduce the HIV Reservoir

In a recent Science Advances paper, researchers from the University of Lausanne, with collaborators at the University Hospital of Zurich, explored whether CAR-T cells could be redirected against a cellular marker of the HIV reservoir, programmed cell death protein 1 (PD-1), rather than viral proteins. As PD-1 is enriched on CD4⁺ T-cell populations which are known to harbor persistent HIV in tissues and blood, the authors sought to investigate new HIV cure strategies by asking whether selective depletion of PD-1⁺ reservoir-containing cells could reduce durable viral persistence.

Two second-generation 4-1BB CAR constructs using single-chain variable fragments from distinct anti–PD-1 antibodies were generated with a blocking PD-1 CAR that interferes with PD-1/PD-L1 binding, and a nonblocking PD-1 CAR that recognizes a separate epitope. In vitro experiments showed that CAR function depended strongly on epitope and avidity. The blocking CAR showed higher sensitivity, trogocytosis, and cytotoxicity against PD-1⁺ target cells. The nonblocking CAR showed more intermediate activity that may offer safety advantages. Importantly, PD-1 intracellular signaling itself did not appear to inhibit CAR-T activation. Because CD4⁺ CAR-T cells can be infected by HIV, the team also incorporated gene-editing strategies, including CD4 disruption, to reduce infection prior to in vivo testing.

In HIV-infected humanized mice, anti–PD-1 CAR-T cells produced measurable in vivo effects after ART interruption. Across all enrolled animals, viral rebound was delayed in bPD1-CAR treated mice compared to untransduced controls (n=13 vs. n=9; p=0.0309), with a similar but nonsignificant trend for nbPD1-CAR treatment (n=11; p=0.082). Among mice completing the study, plasma viral-load tracking included controls (n=6), bPD1-CAR mice (n=9), and nbPD1-CAR mice (n=7); three treated animals (two bPD1-CAR and one nbPD1-CAR) maintained undetectable viremia until 6–8 weeks after ART withdrawal. CAR-T cells remained detectable up to 70 days after adoptive transfer in 33% of bPD1-CAR and 57% of nbPD1-CAR recipients, predominantly as effector-memory CD8⁺ cells. Viral control correlated with CAR-T detection in blood, spleen, and bone marrow, while CD4+PD-1⁺ cell persistence inversely correlated with both viral control and CAR-T expansion. Integrated HIV DNA in sorted tissue CD4⁺ cells also correlated with time to rebound (p=0.0133; r²=0.6673). Together, these findings provide quantitative evidence that PD-1–targeted CAR-T persistence is linked to depletion of reservoir-enriched cells and delayed HIV recrudescence.

Reference:

Ermellino L, Banga R, Georgakis S, et al. Targeting PD-1⁺ T cells with chimeric antigen receptors to reduce the HIV reservoir. Sci Adv. 2026;12(17):eaeb7602. http:doi.org/10.1126/sciadv.aeb7602