Ryo Hanajiri1, Gelina M Sani1, Devin Saunders1, Patrick J Hanley1,2,3, Abha Chopra4,5, Simon A Mallal4,5, Stanislav V Sosnovtsev6, Jeffrey I Cohen6, Kim Y Green6, Catherine M Bollard1,2,3, Michael D Keller1,2,7. 1. Center for Cancer and Immunology Research, Children's National Health System, Washington, District of Columbia, USA. 2. GW Cancer Center, George Washington University, Washington, District of Columbia, USA. 3. Division of Blood and Marrow Transplantation, Children's National Health System, Washington, District of Columbia, 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, Tennessee, USA. 6. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 7. Division of Allergy and Immunology, Children's National Health System, Washington, District of Columbia, 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 this 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: Norovirus-specific T cells 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. Norovirus-specific T cells comprised both CD4+ and CD8+ T cells that expressed markers for central memory and effector memory phenotype with minimal expression of coinhibitory molecules, and they 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.
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 this 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: Norovirus-specific T cells 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. Norovirus-specific T cells comprised both CD4+ and CD8+ T cells that expressed markers for central memory and effector memory phenotype with minimal expression of coinhibitory molecules, and they 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.
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