Research Article: Broadly neutralizing antibody-secreting CAR-T cells elicit Fc-mediated effector functions in vitro and suppress HIV in humanized mice
Abstract:
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.
Introduction:
Human immunodeficiency virus (HIV) remains a major public health issue, affecting 40.8 million adults and children globally ( 1 ). While antiretroviral therapy (ART) suppresses the virus and improves life expectancy of people living with HIV (PLWH), it is not curative ( 2 ). HIV forms stable latent reservoirs during early infection and ART interruption leads to viral rebound, necessitating lifelong treatment ( 3 – 6 ). However, long-term ART administration is associated with cumulative toxicities, increased risk…
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