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SARS-CoV-2 infected cells present HLA-I peptides from canonical and out-of-frame ORFs

View ORCID ProfileShira Weingarten-Gabbay, View ORCID ProfileSusan Klaeger, View ORCID ProfileSiranush Sarkizova, Leah R. Pearlman, Da-Yuan Chen, Matthew R. Bauer, Hannah B. Taylor, Hasahn L. Conway, Christopher H. Tomkins-Tinch, View ORCID ProfileYaara Finkel, View ORCID ProfileAharon Nachshon, Matteo Gentili, Keith D. Rivera, View ORCID ProfileDerin B. Keskin, Charles M. Rice, View ORCID ProfileKarl R. Clauser, View ORCID ProfileNir Hacohen, View ORCID ProfileSteven A. Carr, View ORCID ProfileJennifer G. Abelin, View ORCID ProfileMohsan Saeed, Pardis C. Sabeti
doi: https://doi.org/10.1101/2020.10.02.324145
Shira Weingarten-Gabbay
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
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  • ORCID record for Shira Weingarten-Gabbay
  • For correspondence: shirawg@broadinstitute.org sklaeger@broadinstitute.org msaeed1@bu.edu
Susan Klaeger
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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  • ORCID record for Susan Klaeger
  • For correspondence: shirawg@broadinstitute.org sklaeger@broadinstitute.org msaeed1@bu.edu
Siranush Sarkizova
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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  • ORCID record for Siranush Sarkizova
Leah R. Pearlman
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Da-Yuan Chen
3Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
4National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
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Matthew R. Bauer
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Harvard Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
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Hannah B. Taylor
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Hasahn L. Conway
3Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
4National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
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Christopher H. Tomkins-Tinch
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
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Yaara Finkel
6Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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  • ORCID record for Yaara Finkel
Aharon Nachshon
6Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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Matteo Gentili
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Keith D. Rivera
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Derin B. Keskin
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
7Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
8Health Informatics Lab, Metropolitan College, Boston University, Boston, MA, USA
9Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Charles M. Rice
10Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
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Karl R. Clauser
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Nir Hacohen
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
11Center for Cancer Immunology, Massachusetts General Hospital, Boston, MA, USA
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Steven A. Carr
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Jennifer G. Abelin
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Mohsan Saeed
3Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
4National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
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  • For correspondence: shirawg@broadinstitute.org sklaeger@broadinstitute.org msaeed1@bu.edu
Pardis C. Sabeti
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
12Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA
13Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA
14Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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ABSTRACT

T cell-mediated immunity may play a critical role in controlling and establishing protective immunity against SARS-CoV-2 infection; yet the repertoire of viral epitopes responsible for T cell response activation remains mostly unknown. Identification of viral peptides presented on class I human leukocyte antigen (HLA-I) can reveal epitopes for recognition by cytotoxic T cells and potential incorporation into vaccines. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two human cell lines at different times post-infection using mass spectrometry. We found HLA-I peptides derived not only from canonical ORFs, but also from internal out-of-frame ORFs in Spike and Nucleoprotein not captured by current vaccines. Proteomics analyses of infected cells revealed that SARS-CoV-2 may interfere with antigen processing and immune signaling pathways. Based on the endogenously processed and presented viral peptides that we identified, we estimate that a pool of 24 peptides would provide one or more peptides for presentation by at least one HLA allele in 99% of the human population. These biological insights and the list of naturally presented SARS-CoV-2 peptides will facilitate data-driven selection of peptides for immune monitoring and vaccine development.

Competing Interest Statement

S.W-G., S.K., S.S., K.R.C, N.H., S.A.C, J.G.A, M.S., and P.C.S are named co-inventors on a patent application related to immunogenic compositions of this manuscript filed by The Broad Institute that is being made available in accordance with COVID-19 technology licensing framework to maximize access to university innovations. D.B.K. has previously advised Neon Therapeutics and has received consulting fees from Neon Therapeutics. D.B.K. owns equity in AduroBiotech, Agenus Inc., Armata pharmaceuticals, Breakbio Corp., Biomarin Pharmaceutical Inc.,Bristol Myers Squibb Com., Celldex Therapeutics Inc., Editas Medicine Inc., Exelixis Inc., Gilead Sciences Inc., IMV Inc., Lexicon Pharmaceuticals Inc., Moderna Inc. and Regeneron Pharmaceuticals. D.B.K. receives SARS-CoV-2 research support from BeiGene for an unrelated project to this publication. N.H. is a founder of Neon Therapeutics, Inc. (now BioNTech US), was a member of its scientific advisory board, and holds shares. N.H. is also an advisor for IFM therapeutics. S.A.C is a member of the scientific advisory boards of Kymera, PTM BioLabs and Seer and a scientific advisor to Pfizer and Biogen. J.G.A is a past employee and shareholder of Neon Therapeutics, Inc. (now BioNTech US). P.C.S. is a co-founder and shareholder of Sherlock Biosciences, and is a non-executive board member and shareholder of Danaher Corporation.

Footnotes

  • ↵* co-first authors

  • ↵† co-senior authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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SARS-CoV-2 infected cells present HLA-I peptides from canonical and out-of-frame ORFs
Shira Weingarten-Gabbay, Susan Klaeger, Siranush Sarkizova, Leah R. Pearlman, Da-Yuan Chen, Matthew R. Bauer, Hannah B. Taylor, Hasahn L. Conway, Christopher H. Tomkins-Tinch, Yaara Finkel, Aharon Nachshon, Matteo Gentili, Keith D. Rivera, Derin B. Keskin, Charles M. Rice, Karl R. Clauser, Nir Hacohen, Steven A. Carr, Jennifer G. Abelin, Mohsan Saeed, Pardis C. Sabeti
bioRxiv 2020.10.02.324145; doi: https://doi.org/10.1101/2020.10.02.324145
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SARS-CoV-2 infected cells present HLA-I peptides from canonical and out-of-frame ORFs
Shira Weingarten-Gabbay, Susan Klaeger, Siranush Sarkizova, Leah R. Pearlman, Da-Yuan Chen, Matthew R. Bauer, Hannah B. Taylor, Hasahn L. Conway, Christopher H. Tomkins-Tinch, Yaara Finkel, Aharon Nachshon, Matteo Gentili, Keith D. Rivera, Derin B. Keskin, Charles M. Rice, Karl R. Clauser, Nir Hacohen, Steven A. Carr, Jennifer G. Abelin, Mohsan Saeed, Pardis C. Sabeti
bioRxiv 2020.10.02.324145; doi: https://doi.org/10.1101/2020.10.02.324145

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