HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-...HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications.Here,we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27(3BE)CAR construct that enabled the expression of programmed cell death protein(PD-1)-blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env.Compared with T cells expressing 3BNC117-CAR alone,3BE CAR-T cells showed greater cytotoxic activity against HIV Envt cells with stronger proliferation capability,higher killing efficiency,and enhanced cytokine secretion in the presence of HIV Env-expressing cells.Furthermore,we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env^(+) cells in vivo without the occurrence of severe graft-versus-host disease(GvHD)in NSG mice.These data suggest that we have provided a feasible approach to the generation of“off-theshelf”anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy,which can be a powerful therapeutic candidate for the functional cure of HIV.展开更多
基金funded by the National Natural Science Foundation of China(81761128020 and 82041001)the National Grand Program on Key Infectious Diseases(2017ZX10202102-002).
文摘HIV-specific chimeric antigen receptor(CAR)T-cells have been developed to target HIV-1 infected CD4t T-cells that express HIV Env proteins.However,T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications.Here,we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27(3BE)CAR construct that enabled the expression of programmed cell death protein(PD-1)-blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env.Compared with T cells expressing 3BNC117-CAR alone,3BE CAR-T cells showed greater cytotoxic activity against HIV Envt cells with stronger proliferation capability,higher killing efficiency,and enhanced cytokine secretion in the presence of HIV Env-expressing cells.Furthermore,we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env^(+) cells in vivo without the occurrence of severe graft-versus-host disease(GvHD)in NSG mice.These data suggest that we have provided a feasible approach to the generation of“off-theshelf”anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy,which can be a powerful therapeutic candidate for the functional cure of HIV.
