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

Author:

Promsote Wanwisa,Xu Ling,Hataye JasonORCID,Fabozzi Giulia,March Kylie,Almasri Cassandra G.,DeMouth Megan E.,Lovelace Sarah E.,Talana Chloe AdriennaORCID,Doria-Rose Nicole A.ORCID,McKee Krisha,Hait Sabrina Helmold,Casazza Joseph P.ORCID,Ambrozak David,Beninga Jochen,Rao Ercole,Furtmann Norbert,Birkenfeld Joerg,McCarthy ElizabethORCID,Todd John-Paul,Petrovas ConstantinosORCID,Connors MarkORCID,Hebert Andrew T.,Beck Jeremy,Shen Junqing,Zhang Bailin,Levit MikhailORCID,Wei Ronnie R.,Yang Zhi-yongORCID,Pegu AmarendraORCID,Mascola John R.,Nabel Gary J.ORCID,Koup Richard A.

Abstract

AbstractAgents 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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