Efficient expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates

Sandra Dross, Department of Microbiology, University of Washington, Seattle, WA, United States.
Rasika Venkataraman, Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, United States.
Shabnum Patel, Center for Cancer and Immunology Research, Children's National Hospital and Department of Pediatrics, The George Washington University, Washington, DC, United States.
Meei-Li Huang, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital and Department of Pediatrics, The George Washington University, Washington, DC, United States.
Margherita Rosati, Human Retrovirus Section, Vaccine Branch, National Cancer Institute at Frederick, Frederick, MD, United States.
George N. Pavlakis, Human Retrovirus Section, Vaccine Branch, National Cancer Institute at Frederick, Frederick, MD, United States.
Barbara K. Felber, Human Retrovirus Pathogenesis Section, Vaccine Branch, National Cancer Institute at Frederick, Frederick, MD, United States.
Katharine J. Bar, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
George M. Shaw, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Keith R. Jerome, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
James I. Mullins, Department of Microbiology, University of Washington, Seattle, WA, United States.
Hans-Peter Kiem, Washington National Primate Research Center, Seattle, WA, United States.
Deborah Heydenburg Fuller, Department of Microbiology, University of Washington, Seattle, WA, United States.
Christopher W. Peterson, Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, United States.

Document Type

Journal Article

Publication Date

1-1-2023

Journal

Frontiers in immunology

Volume

14

DOI

10.3389/fimmu.2023.1188018

Keywords

DNA vaccine; HIV-1 cure; antigen-specific T cells; cell therapies; nonhuman primate models; rhesus macaque; therapeutic vaccines

Abstract

HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells' recognition of immunodominant but variable regions of the virus, which facilitates viral escape mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells an cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing -expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells' predominant CD8 effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.

Department

Pediatrics

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