Journal
CELL
Volume 184, Issue 15, Pages 3962-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.05.046
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Funding
- National Institute of Allergy and Infectious Diseases [U19AI110818, U19AI082630]
- National Cancer Institute Clinical Proteomic Tumor Analysis Consortium grants [NIH/NCI U24-CA210986, NIH/NCI U01 CA214125, NIH/NCI U24CA210979]
- Human Frontier Science Program fellowship [LT-000396/2018]
- EMBO non-stipendiary long-term fellowship [ALTF 883-2017]
- Gruss-Lipper postdoctoral fellowship
- Zuckerman STEM Leadership Program fellowship
- Rothschild postdoctoral fellowship
- National Science Foundation [1745303]
- EMBO long-term fellowship [ALTF 486-2018]
- Cancer Research Institute/Bristol-Myers Squibb [CRI2993]
- Emerson Collective
- NIH/NCI [R21 CA216772-01A1]
- G. Harold and Leila Y. Mathers Charitable Foundation
- Bawd Foundation
- NIH NIAID [3 R01-AI091707-10S1]
- Boston University
- Frederick National Laboratory for Cancer Research [HHSN261200800001E]
- Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research
- Mark and Lisa Schwartz Foundation
- Massachusetts Consortium for Pathogen Readiness
- Ragon Institute of MGH, MIT and Harvard
- Direct For Education and Human Resources
- Division Of Graduate Education [1745303] Funding Source: National Science Foundation
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T cell-mediated immunity plays a crucial role in controlling SARS-CoV-2 infection, with some peptides derived from internal out-of-frame ORFs in spike and nucleocapsid eliciting stronger T cell responses than canonical peptides. Early expressed viral proteins contribute more to HLA-I presentation and immunogenicity, providing insights for vaccine development and immune monitoring.
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.
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