Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections
Wanwisa Promsote, Ling Xu, Jason Hataye, Giulia Fabozzi, Kylie March, Cassandra Almasri, Megan Demouth, Sarah Lovelace, Chloe Adrienna Talana, Nicole A. Doria‐Rose, Krisha McKee, Sabrina Helmold Hait, Joseph P. Casazza, David R. Ambrozak, Jochen Beninga, Ercole Rao, Norbert Furtmann, Jörg Birkenfeld, Elizabeth McCarthy, John-Paul Todd, Constantinos Petrovas, Mark Connors, Andrew Hebert, Jeremy M. Beck, Junqing Shen, Bailin Zhang, Mikhail Levit, Ronnie R. Wei, Zhiyong Yang, Amarendra Pegu, John R. Mascola, Gary J. Nabel, Richard A. Koup
Abstract
Abstract 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/αCD3-αCD28, 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/αCD3-αCD28, 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.