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), human immunodeficiency virus (HIV) persists in long-lived viral reservoirs, requiring lifelong treatment and highlighting the need for curative strategies. Viral persistence across anatomically distinct reservoirs, together with HIV-associated immune dysregulation, supports the development of combination immunotherapies capable of acting through multiple antiviral mechanisms. Here, we developed and evaluated a Hybrid chimeric antigen receptor (CAR) platform that combines the targeted cytotoxicity of CAR-T cells with the secretion of broadly neutralizing antibodies (bNAbs). We assessed the capacity of Hybrid CAR-T cells to eliminate HIV-infected cells, neutralize free virus, and recruit Fc-mediated effector mechanisms in vitro, and evaluated their antiviral activity in humanized mice. In vitro, Hybrid CAR-T cells eliminated HIV-infected CD4+ T cells, while 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 and detectable circulating bNAbs in plasma. Collectively, these findings demonstrate that Hybrid CAR-T cells can bridge cellular and humoral immunity by combining direct killing of HIV-infected cells with antibody-mediated antiviral activity. This dual-function platform represents a synergistic next-generation immunotherapy with translational potential as a strategy toward a functional HIV cure.