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 G. Almasri, Megan E. DeMouth, Sarah E. Lovelace, Chloe Adrienna Talana, Nicole A. Doria-Rose, Krisha McKee, Sabrina Helmold Hait, Joseph P. Casazza, David Ambrozak, Jochen Beninga, Ercole Rao, Norbert Furtmann, Joerg Birkenfeld, Elizabeth McCarthy, John-Paul Todd, Constantinos Petrovas, Mark Connors, Andrew T. Hebert, Jeremy Beck, Junqing Shen, Bailin Zhang, Mikhail Levit, Ronnie R. Wei, Zhi-yong Yang, Amarendra Pegu, John R. Mascola, Gary J. Nabel () and Richard A. Koup ()
Additional contact information
Wanwisa Promsote: National Institutes of Health
Ling Xu: Sanofi
Jason Hataye: National Institutes of Health
Giulia Fabozzi: National Institutes of Health
Kylie March: National Institutes of Health
Cassandra G. Almasri: National Institutes of Health
Megan E. DeMouth: National Institutes of Health
Sarah E. Lovelace: National Institutes of Health
Chloe Adrienna Talana: National Institutes of Health
Nicole A. Doria-Rose: National Institutes of Health
Krisha McKee: National Institutes of Health
Sabrina Helmold Hait: National Institutes of Health
Joseph P. Casazza: National Institutes of Health
David Ambrozak: National Institutes of Health
Jochen Beninga: Sanofi
Ercole Rao: Sanofi
Norbert Furtmann: Sanofi
Joerg Birkenfeld: Sanofi
Elizabeth McCarthy: National Institutes of Health
John-Paul Todd: National Institutes of Health
Constantinos Petrovas: National Institutes of Health
Mark Connors: NIAID, NIH
Andrew T. Hebert: Sanofi
Jeremy Beck: Sanofi
Junqing Shen: Sanofi
Bailin Zhang: Sanofi
Mikhail Levit: Sanofi
Ronnie R. Wei: Sanofi
Zhi-yong Yang: Sanofi
Amarendra Pegu: National Institutes of Health
John R. Mascola: National Institutes of Health
Gary J. Nabel: Sanofi
Richard A. Koup: National Institutes of Health

Nature Communications, 2023, vol. 14, issue 1, 1-13

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.

Date: 2023
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DOI: 10.1038/s41467-023-39265-z

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