T cell receptor–targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice
Mengyan Li, … , Steven C. Almo, Harris Goldstein
Mengyan Li, … , Steven C. Almo, Harris Goldstein
Published October 21, 2021
Citation Information: J Clin Invest. 2021;131(23):e141051. https://doi.org/10.1172/JCI141051.
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Research Article AIDS/HIV Immunology

T cell receptor–targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice

Abstract

To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB–specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.

Authors

Mengyan Li, Scott J. Garforth, Kaitlyn E. O’Connor, Hang Su, Danica M. Lee, Alev Celikgil, Rodolfo J. Chaparro, Ronald D. Seidel, R. Brad Jones, Ravit Arav-Boger, Steven C. Almo, Harris Goldstein

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Figure 8

In vivo treatment with synTac expands pp65- and SL9-specific CD8+ T cells and inhibits in vivo CMV and HIV infection.

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In vivo treatment with synTac expands pp65- and SL9-specific CD8+ T cell...
(A) NSG mice (n = 17 mice) intrasplenically injected with HGLK055 PBMCs were untreated (n = 8 mice) or intravenously injected with pp65-αCD28-synTac (4 mg/kg, n = 9 mice). One week later, CMV-luc–infected MRC-5 cells were intrasplenically injected into the indicated mice. On day 10, the mouse spleens were harvested to quantify (B) pp65-specific CD8+ T cells by flow cytometry and (C) CMV infection by luciferase quantification. Dot plots in B and C show percentage of pp65-specific CD8+ T cells and CMV luciferase levels in the mouse spleens and mean ± SEM, respectively, with percentage of suppression versus untreated mice shown. (D) NSG mice (n = 13 mice) intrasplenically injected with PBMCs (32 × 106) from HIV-seropositive donor 619 and CD8+ T cell–depleted PBMCs (14 × 106) from donor HGLK67 were untreated (n = 7 mice) or intravenously treated with SL9-αCD28-synTac at 0.4 mg/kg (n = 6 mice). The mice received no ART. Two weeks later the mice were bled and 3 days later the mouse spleens were harvested. (E) HIV viral loads in the plasma were quantified and values for each mouse are shown with mean ± SEM for the untreated and SL9-αCD28-synTac–treated mice and percentage of reduction of the plasma HIV viral loads in the SL9-αCD28-synTac–treated mice as compared with the untreated mice. (F) The percentage of human CD45+CD3+ and CD8+ SL9-specific T cells in the spleens of each mouse are shown with mean ± SEM for the untreated and SL9-αCD28-synTac–treated mice. Statistical significance was determined by the Wilcoxon Mann-Whitney U test.