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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 7

Viral clearance assay detects HIVxCD3 DART–redirected CD8+ T cell clearance of JR-CSF– or AR virus–infected CD4+ cells using lymphocytes from HIV-infected ART suppressed patients.

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Viral clearance assay detects HIVxCD3 DART–redirected CD8+ T cell cleara...
CD4+ depleted T cells from HIV-infected, ART-suppressed patients were activated with PHA and infected with HIV-1 subtype B clone JR-CSF (A–C) or AR virus isolates (D–F), and then incubated without (A and D) or with autologous CD8+ T effector cells at E/T ratios of 1:10 (B and E) or 1:1 (C and F) in the absence (No DART) or presence of HIVxCD3 (A32xCD3, 7B2xCD3) or control (7B2x4420, 4420xCD3) DARTs at a concentration of 100 ng/ml for 7 days. Combo indicates a 1:1 cocktail of 7B2xCD3 and A32xCD3 at a total concentration of 100 ng/ml. Each bar represents the log-fold reduction of p24 detected in culture supernatants, calculated as the log (p24 levels of infected target cells divided by p24 levels of the test condition). (G) Schematic of gating strategy to identify live/CD3+CD4+CD107+ effector (TFL4–) T cells after their incubation with HIV-1 JR-CSF–infected target cells in presence of DARTs for 6 hours. (H) The percentage of live/effector cells (TFL4–)/CD3+/CD4+/107a+ cells following a 6-hour incubation with the indicated DARTs and JR-CSF–infected targets in n = 4 patients. Error bars represent ± SEM of n = 8 (A–C, except for combo [n = 5] and 7B2x4420 [n = 6]), n = 5 (D–F), and n = 4 (G and H). *P < 0.05 with Dunnett’s test for multiple comparisons.

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

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