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Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs
Open accessAbstract
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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“A recent study revealed that cryptic epitopes, originating from out-of-frame open reading frame translation during SARS-CoV-2 infection,73 can be modified or lost during codon optimization, leading to either enhanced or diminished immunogenic responses.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [73]
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Metadata
- Authors
- Weingarten-Gabbay, S., Klaeger, S., Sarkizova, S., Pearlman, L. R., Chen, D.-Y., Gallagher, K. M. E., Bauer, M. R., Taylor, H. B., Dunn, W. A., Tarr, C., Sidney, J., Rachimi, S., Conway, H. L., Katsis, K., Wang, Y., Leistritz-Edwards, D., Durkin, M. R., Tomkins-Tinch, C. H., Finkel, Y., Nachshon, A., Gentili, M., Rivera, K. D., Carulli, I. P., Chea, V. A., Chandrashekar, A., Bozkus, C. C., Carrington, M., Lavin-Parsons, K., Parry, B., Lilley, B., Lodenstein, C., McKaig, B., Charland, N., Khanna, H., Margolin, J., Gonye, A., Gushterova, I., Lasalle, T., Sharma, N., Russo, B. C., Rojas-Lopez, M., Sade-Feldman, M., Manakongtreecheep, K., Tantivit, J., Fisher Thomas, M., Bhardwaj, N., Barouch, D. H., Sette, A., Maus, M. V., Rice, C. M., Clauser, K. R., Keskin, D. B., Pregibon, D. C., Hacohen, N., Carr, S. A., Abelin, J. G., Saeed, M., & Sabeti, P. C.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- La Jolla Institute for Immunology (US)
- Boston University (US)
- Massachusetts General Hospital (US)
- Weizmann Institute of Science (IL)
- Dana-Farber Cancer Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Mount Sinai Hospital (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Rockefeller University (US)
- Corresponding author
- Weingarten-Gabbay, Shira
- Klaeger, Susan
- Saeed, Mohsan
- ORCID
- Weingarten-Gabbay, Shira
- Klaeger, Susan
- Sarkizova, Siranush
- Gallagher, Kathleen M.E.
- Bauer, Matthew R.
- Taylor, Hannah B.
- Sidney, John
- Rachimi, Suzanna
- Conway, Hasahn L.
- Leistritz-Edwards, Del
- Durkin, Melissa R.
- Tomkins-Tinch, Christopher H.
- Finkel, Yaara
- Nachshon, Aharon
- Gentili, Matteo
- Rivera, Keith D.
- Carulli, Isabel P.
- Chea, Vipheaviny A.
- Chandrashekar, Abishek
- Bozkus, Cansu Cimen
- Carrington, Mary
- Parry, Blair
- Lilley, Brendan
- McKaig, Brenna
- Charland, Nicole
- Khanna, Hargun
- Margolin, Justin
- Gonye, Anna
- Gushterova, Irena
- Russo, Brian C.
- Sade-Feldman, Moshe
- Manakongtreecheep, Kasidet
- Tantivit, Jessica
- Bhardwaj, Nina
- Barouch, Dan H.
- Sette, Alessandro
- Maus, Marcela V.
- Rice, Charles M.
- Clauser, Karl R.
- Keskin, Derin B.
- Pregibon, Daniel C.
- Hacohen, Nir
- Carr, Steven A.
- Abelin, Jennifer G.
- Saeed, Mohsan
- Sabeti, Pardis C.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 184
- Issue
- 15
- Pages
- 3962-3980.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8173604
- OpenAlex
- W3172192134
- Cited by
- 147
- References
- 103
- Citations by year
- 2026: 6 · 2025: 23 · 2024: 32 · 2023: 38 · 2022: 33 · 2021: 15
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U24-CA210986, U24CA210979, U01 CA214125)
- NIAID (U19AI110818, 3 R01-AI091707-10S1, U19AI082630)
- Cancer Research Institute
- Parker Institute for Cancer Immunotherapy
- Broad Institute
- Frederick National Laboratory for Cancer Research (HHSN261200800001E)
- Human Frontier Science Program (LT-000396/2018)
- European Molecular Biology Organization (ALTF 883-2017)
- Iran National Science Foundation (CRI2993, 1745303, R21 CA216772-01A1, ALTF 486-2018)
- Harvard University
- Gilead Sciences
- National Institutes of Health
- G. Harold and Leila Y. Mathers Charitable Foundation
- Novartis
- Neos Therapeutics
- U.S. Department of Health and Human Services
- Massachusetts Institute of Technology
- Boston University
- BioMarin Pharmaceutical
- Pfizer
- Celldex Therapeutics
- Biogen
- Government of South Australia
- Exelixis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- SARS-CoV-2, T cell epitopes, viral peptide presentation, spike protein, nucleocapsid protein, T cell immunity, humanized mice, COVID-19 pandemic, vaccine development, early viral proteins
- MeSH terms
- A549 Cells, COVID-19, SARS-CoV-2, Alleles, Amino Acid Sequence, Animals, Female, Humans, Kinetics, Male, Peptides, T-Lymphocytes, Histocompatibility Antigens Class I, Open Reading Frames, Antigen Presentation, Epitopes, T-Lymphocyte, Proteome, Mice, HEK293 Cells
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