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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.

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