Using convertibleCAR-T cells programmed with broadly neutralizing antibodies to attack the latent HIV reservoir

One potential approach to achieving a functional HIV cure is to first reduce the size of the reservoir and then engineer an immune response that can effectively control the shrunken reservoir in the absence of antiretroviral therapy. We have constructed fusion proteins, called MicAbodies, comprised of full-length broadly-neutralizing HIV antibodies coupled to a mutated form of ULPB2, a member of the MIC family (ligands for NKG2D receptor). These MicAbodies, selectively engage a variant of NKG2D (iNKG2D) that has been engineered as a chimeric antigen receptor (CAR) and expressed on CD8 T cells (convertibleCAR-T Cells). Together, the HIV-specific MicAbody and the convertibleCAR-T cells can detect and eliminate HIV infected cells. in vivo proof of concept of the platform’s killing capabilities studies in NSG mice exploring convertibleCAR-T efficacy against Raji tumors demonstrated rituximab-based MicAbody as well as convertibleCAR-T dose-dependent control of tumor mass. In HIV-infected primary cells, the cytotoxic effector function of these cells is activated when a MicAbody simultaneously engages both the HIV Env target and iNKG2D-CAR on convertibleCAR-T CD8 T cells. We show that this platform, convertibleCAR-T cells, effectively kill HIV-infected, but not uninfected CD4 T-cells from blood, tonsil or spleen, and only when armed with anti-HIV MicAbodies. ConvertibleCAR-T cells also kill within 48 hours more than half of the inducible reservoir found in blood of HIV-infected individuals on antiretroviral therapy. The modularity of convertibleCAR-T cell system, which allows multiplexing with several anti-HIV antibodies yielding greater breadth and control, makes it a promising tool for attacking the latent HIV reservoir.