Hybrid CARs on the road to HIV cure

Antiretroviral therapy -the current gold standard in HIV treatment- fails to provide a definitive cure. However, cell therapies for HIV are increasingly gaining ground, with the use of Chimeric Antigen Receptors (CARs) being widely explored. CAR-T cell therapies have been successfully applied in oncology, particularly in hematologic malignancies, reaching up to 90% remission. In infectious diseases, all previously explored CAR-based strategies exert a direct killing effect towards infected cells only, leaving cell-free pathogens unaddressed, hence failing to treat viral infections. In this project, we propose an innovative approach, Hybrid CAR, that combines the cytotoxic potential of CAR-T cells with the antiviral properties of broadly neutralizing antibodies (bNAbs). We generated CD4-based Hybrid CAR-T cells, capable of secreting bNAbs, hence both cellular and cell-free viral targets can be preyed on. Except neutralization of cell-free virions, the presence of Fc-IgG1 domain will provide a bridge between adaptive and innate immunity, facilitating Antibody Dependent Cellular Cytotoxicity and Phagocytosis (ADCC and ADCP, respectively). Therefore, the aim of this PhD project will be to explore and evaluate the cytotoxic potency of Hybrid CAR-T cells, along with the neutralization and Fc-mediated properties of secreted antibodies, in vitro, ex vivo (in primary cells derived from both healthy and HIV-infected donors) and in vivo (in an established humanized mouse model).