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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 Article has an altmetric score of 95

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 4

HIVxCD3 DARTs redirect T cell cytotoxicity against CD4+ cells infected with HIV-1 IMCs of different subtypes.

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HIVxCD3 DARTs redirect T cell cytotoxicity against CD4+ cells infected w...
(A–C) DART-concentration dependence. Activated CD4+ T cells from a HIV-1 seronegative donor were infected with HIV-1 subtype B BaL (A), subtype AE CM235 (B), or subtype C 1086.C (C) IMC and incubated for 48 hours with A32xCD3 (red circles), 7B2xCD3 (blue squares), or 4420xCD3 (black diamonds) in the presence of autologous resting CD8+ T cells at an E/T ratio of 33:1 (filled symbols) or in the absence of effector cells (E/T ratio of 0:1) (open symbols). The data are reported as %SL. DART concentrations ranged from 0.001–1,000 ng/ml. (D–F) Time course. The data represent the maximal %SL observed at 6, 24, and 48 hours for each DART against CD4+ T cells infected infected with HIV-1 subtype B BaL (D), subtype AE CM235 (E), or subtype C 1086.C (F) IMC and incubated with autologous resting CD8+ T cells at an E/T ratio of 33:1.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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