HIV-specific chimeric antigen receptor (CAR) T-cell therapy culminated in the development of HIV-resistant (C34-CXCR4+) dual-CAR T-cells, according to a study published in Nature Medicine.
The researchers used a humanised mouse model of HIV infection to iteratively test CD28 and 4-1BB co-stimulation in the context of optimising HIV-specific CAR T-cell therapy, leveraging the mouse model’s ability to support HIV infection.
Initially, 4-1BB-costimulated CAR T-cells demonstrated marked in vivo antigen-driven proliferation and survival, but failed to control viraemia after antiretroviral therapy cessation. After creating a dual-CAR T-cell that simultaneously expresses two CD4-based CARs, it was possible to observe both the cytotoxic potential and cytokine expression of CD28-costimulated CAR T cells and the proliferative capacity of 4-1BB-costimulated CAR T-cells.
Treatment with HIV-resistant dual-CAR T-cells resulted in a reduction in HIV burden in a variety of tissues and cell types, suggesting for the first time that a CAR T-cell therapy targeted the HIV reservoir.
The authors say that these findings provide critical insight into the iterative development of an engineered T-cell based therapy for HIV.