Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/alpha CD3-alpha CD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4(+) and CD8(+) T cells. Co-culturing CD4(+) with autologous CD8(+) T cells from ART-suppressed HIV+ donors with N6/alpha CD3-alpha CD28, results in activation of latently-infected cells and their elimination by activated CD8(+) T cells. This trispecific antibody mediates CD4(+) and CD8(+) T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection. One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV-1 infected cells for elimination by T cells as an alternative strategy for HIV cure.