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J Infect Dis. 2019 Sep 28. pii: jiz491. doi: 10.1093/infdis/jiz491. [Epub ahead of print]

Generation of Norovirus-Specific T-Cells from Human Donors with Extensive Cross-Reactivity to Variant Sequences: Implications for Immunotherapy.

Author information

1
Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA.
2
GW Cancer Center, George Washington University, Washington, DC, USA.
3
Division of Blood and Marrow Transplantation, Children's National Health System, Washington, DC, USA.
4
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia.
5
Division of Infectious Diseases, Department of Medicine Vanderbilt University School of Medicine, Nashville, TN, USA.
6
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
7
Division of Allergy and Immunology, Children's National Health System, Washington, DC, USA.

Abstract

BACKGROUND:

Chronic norovirus infection in immunocompromised patients can be severe, and presently there is no effective treatment. Adoptive transfer of virus-specific T-cells has proven to be safe and effective for the treatment of many viral infections, and could represent a novel treatment approach for chronic norovirus infection. Hence, we sought to generate human norovirus-specific T-cells (NSTs) that can recognize different viral sequences.

METHODS:

NSTs were generated from peripheral blood of healthy donors by stimulation with overlapping peptide libraries spanning the entire coding sequence of the norovirus genome.

RESULTS:

We successfully generated T-cells targeting multiple norovirus antigens with a mean 4.2 ± 0.5-fold expansion after 10 days. NSTs were comprised of both CD4+ and CD8+ T-cells that expressed markers for central memory and effector memory phenotype with minimal expression of co-inhibitory molecules, and were polyfunctional based on cytokine production. We identified novel CD4 and CD8-restricted immunodominant epitopes within NS6 and VP1 antigens. Furthermore, NSTs showed a high degree of cross-reactivity to multiple variant epitopes from clinical isolates.

CONCLUSIONS:

Our findings identify immunodominant human norovirus T-cell epitopes and demonstrate that it is feasible to generate potent NSTs from third party donors for use in antiviral immunotherapy.

KEYWORDS:

Adoptive immunotherapy; Norovirus; Primary Immunodeficiency; T-cells; Transplantation

PMID:
31562500
DOI:
10.1093/infdis/jiz491

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