CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence

Abstract

CAR T-cell therapies have demonstrated immense clinical successes for B-cell and plasma-cell malignancies. We tested their impact on the viral reservoir in a macaque model of HIV persistence, comparing the function of CD20 CAR T cells between animals infected with simian/human immunodeficiency virus (SHIV) and uninfected controls. We focused on the potential of this approach to disrupt B-cell follicles (BCFs), exposing infected cells for immune clearance. In SHIV-infected animals, CAR T cells were highly functional with rapid expansion and trafficking to tissue-associated viral sanctuaries including BCFs and gut-associated lymphoid tissues (GALT). CD20 CAR T-cells potently ablated BCFs and depleted lymph node-associated T follicular helper (T_FH) cells, with complete restoration of BCF architecture and T_FH cells following CAR T-cell contraction. BCF ablation decreased the splenic SHIV reservoir but was insufficient for effective reductions in systemic viral reservoirs. Although associated with moderate hematologic toxicity, CD20 CAR T-cells were well tolerated in SHIV-infected and control animals, supporting the feasibility of this therapy in people living with HIV with underlying B-cell malignancies. Our findings highlight the unique ability of CD20 CAR T cells to safely and reversibly unmask T_FH cells within BCF sanctuaries, informing future combinatorial HIV cure strategies designed to augment antiviral efficacy.