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Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs.

ABSTRACT: 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.

SUBMITTER: Weingarten-Gabbay S

PROVIDER: S-EPMC8173604 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs

Project description:Weingarten-Gabbay S, Klaeger S, Sarkizova S, Pearlman LR, Chen D, Gallagher K, Bauer MR, Taylor HB, W. Augustine Dunn WA, Tarr C, Sidney J, Rachimi S, Conway HL, Katsis K, Yuntong Wang Y, Leistritz-Edwards D, Durkin MR, Tomkins-Tinch CH, Finkel Y, Nachshon A, Gentili M, Rivera KD, Carulli IP, Chea VA, Chandrashekar A, Bozkus CC, Carrington M, MGH COVID-19 Collection & Processing Team, Bhardwaj N, Barouch DH, Sette A, Maus MV, Rice CM, Clauser KR, Keskin DB, Pregibon DC, Hacohen N, Carr SA, Abelin JG, Saeed M, Sabeti PC. 2021 T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection; yet the repertoire of naturally processed and presented viral epitopes on HLA class 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 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 COVID-19 patients 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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