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Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells
Julia A.M. Sung, … , David M. Margolis, Guido Ferrari
Julia A.M. Sung, … , David M. Margolis, Guido Ferrari
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4077-4090. https://doi.org/10.1172/JCI82314.
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Research Article AIDS/HIV

Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells

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Abstract

Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell–mediated clearance of HIV-1–infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity–mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected–patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals.

Authors

Julia A.M. Sung, Joy Pickeral, Liqin Liu, Sherry A. Stanfield-Oakley, Chia-Ying Kao Lam, Carolina Garrido, Justin Pollara, Celia LaBranche, Mattia Bonsignori, M. Anthony Moody, Yinhua Yang, Robert Parks, Nancie Archin, Brigitte Allard, Jennifer Kirchherr, JoAnn D. Kuruc, Cynthia L. Gay, Myron S. Cohen, Christina Ochsenbauer, Kelly Soderberg, Hua-Xin Liao, David Montefiori, Paul Moore, Syd Johnson, Scott Koenig, Barton F. Haynes, Jeffrey L. Nordstrom, David M. Margolis, Guido Ferrari

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Figure 1

HIVxCD3 DART structure.

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HIVxCD3 DART structure.
(A and B) These DART molecules contain an anti–H...
(A and B) These DART molecules contain an anti–HIV-1 binding arm (A32 or 7B2) combined with an anti-CD3 binding arm (hXR32). They are composed of 2 polypeptide chains: one with the VL of anti-CD3 linked to the VH of anti-HIV; the second with the VL of anti-HIV linked to the VH of anti-CD3. The carboxy termini of the chains have an interchain disulfide bond and paired oppositely charged E-coil/K-coil dimerization domains. Control DARTs have one of the arms replaced by an irrelevant one derived from an anti-FITC antibody (4420) or from an anti-RSV antibody, palivizumab (RSV) sequence. (C) Schematic representation of HIVxCD3 DART binding to 2 distinct antigens simultaneously and redirecting the cytotoxic T cells (effectors) to lyse the Env-expressing, HIV-1–infected cells (targets).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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