Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model.

Driving a new HIV therapy forward: CAR T cells, which are now associated with cancer therapy, were previously investigated as a treatment for HIV almost 30 years ago. Now wielding new technology and biological knowledge, Anthony-Gonda et al. report a series of multispecific anti-HIV CARs. These CARs target different portions of the HIV envelope protein and were able to eliminate diverse strains of HIV in vitro, even those that are resistant to potent broadly neutralizing antibodies. The CAR T cells are resistant to HIV infection and were able to control HIV in a humanized mouse model. The persistent surveillance capabilities of CAR T cells suggest that this therapy may one day be able to eradicate HIV in an infected person. Adoptive immunotherapy using chimeric antigen receptor–modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1–based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4⁺ T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection. [ABSTRACT FROM AUTHOR]