Broadly neutralizing antibody-secreting CAR-T cells elicit Fc-mediated effector functions in vitro and suppress HIV in humanized mice

Despite significant advances in antiretroviral therapy (ART) that have transformed human immunodeficiency virus (HIV) infection from a fatal diagnosis to a manageable chronic condition, the persistent viral reservoir necessitates lifelong treatment underscoring the critical need for curative interventions. Viral persistence within anatomically distinct reservoirs, coupled with HIV-associated immune dysregulation accentuates the need for innovative combination immunotherapies that can act through multiple mechanisms. We introduce the Hybrid chimeric antigen receptor (CAR) platform: a dual-function immunotherapy that combines the targeted cytotoxicity of CAR-T cells with the secretion of broadly neutralizing antibodies (bNAbs). This approach enables direct elimination of HIV-infected cells, neutralization of free virus and Fc-mediated effector recruitment. In vitro, Hybrid CAR-T cells eliminated HIV-infected CD4+ T cells while the secreted bNAbs neutralized HIV and mediated robust Fc-effector functions including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In humanized mice, Hybrid CAR-T treatment achieved more than a 9-fold reduction in plasma viremia, accompanied by a significant decrease in viral levels across tissues, with circulating bNAbs detected in plasma. Collectively, these findings highlight the potential of Hybrid CAR-T cells as a synergistic next-generation therapeutic that bridges cellular and humoral immunity, supporting their translational promise as a strategy toward functional HIV cure.