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Volume 26, Issue 6, Pages 1435-1446 (June 2018) HIV-Specific T Cells Generated from Naive T Cells Suppress HIV In Vitro and Recognize Wide Epitope Breadths Shabnum Patel, Elizabeth Chorvinsky, Shuroug Albihani, Conrad Russell Cruz, R. Brad Jones, Elizabeth J. Shpall, David M. Margolis, Richard F. Ambinder, Catherine M. Bollard Molecular Therapy Volume 26, Issue 6, Pages 1435-1446 (June 2018) DOI: 10.1016/j.ymthe.2018.04.009 Copyright © 2018 Terms and Conditions

Molecular Therapy 2018 26, 1435-1446DOI: (10.1016/j.ymthe.2018.04.009) Copyright © 2018 Terms and Conditions

Figure 1 HNA-Ts and CB-Ts Are Derived from the Naive Compartment, Expand to Clinically Relevant Levels, and Demonstrate HIV Specificity (A) HNA-T generated from the naive T cell compartment (red) produced HIV-specific T cells compared to the non-naive compartment (blue). HNA-Ts displayed significant IFNγ secretion to GNP stimulation (p < 0.0001) compared to negative controls CTL only and actin. (B) CB-Ts produced significant levels of IFNγ in response to GNP stimulation compared to CTL only (p < 0.0001). (C) HPA-Ts were manufactured from HIV+ HLA-A02 individuals for use in comparative studies later on and demonstrated significant IFNγ secretion to GNP stimulation (p < 0.0001). Molecular Therapy 2018 26, 1435-1446DOI: (10.1016/j.ymthe.2018.04.009) Copyright © 2018 Terms and Conditions

Figure 2 Phenotyping of HIV-Specific T Cell Products Reveals Differences in Composition and Minimal Expression of Exhaustion Markers (A and B) HNA-Ts (A) and CB-Ts (B) display a primarily CD3+ phenotype, comprised of substantial CD4+ and CD8+ subsets. (C) HPA-Ts are comprised of primarily CD8+ T cells and NK/NKT cells, with a negligible CD4+ population. All three cohorts display skewed effector memory responses and low expression of exhaustion markers. Molecular Therapy 2018 26, 1435-1446DOI: (10.1016/j.ymthe.2018.04.009) Copyright © 2018 Terms and Conditions

Figure 3 HNA-Ts and CB-Ts Demonstrate Cytotoxicity, Suppression of Active HIV Infection In Vitro, and Secretion of Multiple Cytokines (A) HNA-Ts and CB-Ts display specific lysis of GNP-pulsed autologous PHAb targets (red) at comparable levels to HPA-T products. CB-Ts demonstrate dual EBV specificity by specific lysis of unpulsed autologous LCLs (green). Error bars represent the SD of triplicate values. (B) HNA-Ts (n = 4) and CB-Ts (n = 4) demonstrate suppression of active HIV infection in vitro at E:T of 40:1 and 20:1 at day 7. Error bars represent the SD of triplicate values. (C) HNA-T, CB-T, and HPA-T products secrete IL-2, IL-8, IFNγ, and TNF-α in response to GNP stimulation, demonstrating product polyfunctionality. Error bars represent the SD from the mean. Molecular Therapy 2018 26, 1435-1446DOI: (10.1016/j.ymthe.2018.04.009) Copyright © 2018 Terms and Conditions

Figure 4 HLA-A02-Restricted HIV-Specific T Cells Derived from Virus-Naive Donors Do Not Recognize Gag SL9, Despite Forced Expression Manufacturing Methods (A) No SL9-specific HNA-T or CB-T products were generated using forced expression methods with SL9 9-mer peptide. (B) In comparison, GNP-specific HNA-Ts and CB-Ts were generated from the same donors as a control. (C) SL9-specific T cells were produced using our manufacturing methods from an HIV-positive donor (OM9), determined by IFNγ ELISPOT. (D) SL9-specific T cells show low functional avidity on IFNγ ELISPOT, stimulating with progressive dilutions of SL9 9-mer peptide. In this figure, error bars represent the SD. Molecular Therapy 2018 26, 1435-1446DOI: (10.1016/j.ymthe.2018.04.009) Copyright © 2018 Terms and Conditions