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

Author

Listed:
  • Wanwisa Promsote

    (National Institutes of Health)

  • Ling Xu

    (Sanofi
    ModeX Therapeutics Inc.)

  • 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
    FiZ Frankfurt Innovation Center Biotechnology)

  • Elizabeth McCarthy

    (National Institutes of Health)

  • John-Paul Todd

    (National Institutes of Health)

  • Constantinos Petrovas

    (National Institutes of Health
    Lausanne University Hospital (chuv) and University of Lausanne)

  • Mark Connors

    (NIAID, NIH)

  • Andrew T. Hebert

    (Sanofi)

  • Jeremy Beck

    (Sanofi)

  • Junqing Shen

    (Sanofi)

  • Bailin Zhang

    (Sanofi)

  • Mikhail Levit

    (Sanofi)

  • Ronnie R. Wei

    (Sanofi
    ModeX Therapeutics Inc.)

  • Zhi-yong Yang

    (Sanofi
    ModeX Therapeutics Inc.)

  • Amarendra Pegu

    (National Institutes of Health)

  • John R. Mascola

    (National Institutes of Health
    ModeX Therapeutics Inc.)

  • Gary J. Nabel

    (Sanofi
    ModeX Therapeutics Inc.)

  • Richard A. Koup

    (National Institutes of Health)

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.

Suggested Citation

  • 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 & S, 2023. "Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39265-z
    DOI: 10.1038/s41467-023-39265-z
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    References listed on IDEAS

    as
    1. Christopher C. Nixon & Maud Mavigner & Gavin C. Sampey & Alyssa D. Brooks & Rae Ann Spagnuolo & David M. Irlbeck & Cameron Mattingly & Phong T. Ho & Nils Schoof & Corinne G. Cammon & Greg K. Tharp & M, 2020. "Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo," Nature, Nature, vol. 578(7793), pages 160-165, February.
    2. Amarendra Pegu & Mangaiarkarasi Asokan & Lan Wu & Keyun Wang & Jason Hataye & Joseph P. Casazza & Xiaoti Guo & Wei Shi & Ivelin Georgiev & Tongqing Zhou & Xuejun Chen & Sijy O’Dell & John-Paul Todd & , 2015. "Activation and lysis of human CD4 cells latently infected with HIV-1," Nature Communications, Nature, vol. 6(1), pages 1-9, December.
    3. Julia Bergild McBrien & Maud Mavigner & Lavinia Franchitti & S. Abigail Smith & Erick White & Gregory K. Tharp & Hasse Walum & Kathleen Busman-Sahay & Christian R. Aguilera-Sandoval & William O. Thaye, 2020. "Author Correction: Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells," Nature, Nature, vol. 578(7796), pages 21-21, February.
    4. Kirston Barton & Bonnie Hiener & Anni Winckelmann & Thomas Aagaard Rasmussen & Wei Shao & Karen Byth & Robert Lanfear & Ajantha Solomon & James McMahon & Sean Harrington & Maria Buzon & Mathias Lichte, 2016. "Broad activation of latent HIV-1 in vivo," Nature Communications, Nature, vol. 7(1), pages 1-8, November.
    5. Julia Bergild McBrien & Maud Mavigner & Lavinia Franchitti & S. Abigail Smith & Erick White & Gregory K. Tharp & Hasse Walum & Kathleen Busman-Sahay & Christian R. Aguilera-Sandoval & William O. Thaye, 2020. "Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells," Nature, Nature, vol. 578(7793), pages 154-159, February.
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