PMID- 34171305
OWN - NLM
STAT- MEDLINE
DCOM- 20210803
LR  - 20240302
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 184
IP  - 15
DP  - 2021 Jul 22
TI  - Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame 
      ORFs.
PG  - 3962-3980.e17
LID - S0092-8674(21)00701-7 [pii]
LID - 10.1016/j.cell.2021.05.046 [doi]
AB  - 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.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Weingarten-Gabbay, Shira
AU  - Weingarten-Gabbay S
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of 
      Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, 
      USA. Electronic address: shirawg@broadinstitute.org.
FAU - Klaeger, Susan
AU  - Klaeger S
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: 
      sklaeger@broadinstitute.org.
FAU - Sarkizova, Siranush
AU  - Sarkizova S
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Pearlman, Leah R
AU  - Pearlman LR
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Chen, Da-Yuan
AU  - Chen DY
AD  - Department of Biochemistry, Boston University School of Medicine, Boston, MA, 
      USA; National Emerging Infectious Diseases Laboratories, Boston University, 
      Boston, MA, USA.
FAU - Gallagher, Kathleen M E
AU  - Gallagher KME
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
FAU - Bauer, Matthew R
AU  - Bauer MR
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Program in 
      Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, 
      USA.
FAU - Taylor, Hannah B
AU  - Taylor HB
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Dunn, W Augustine
AU  - Dunn WA
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Tarr, Christina
AU  - Tarr C
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Sidney, John
AU  - Sidney J
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology (LJI), La Jolla, CA 92037, USA.
FAU - Rachimi, Suzanna
AU  - Rachimi S
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Conway, Hasahn L
AU  - Conway HL
AD  - Department of Biochemistry, Boston University School of Medicine, Boston, MA, 
      USA; National Emerging Infectious Diseases Laboratories, Boston University, 
      Boston, MA, USA.
FAU - Katsis, Katelin
AU  - Katsis K
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Wang, Yuntong
AU  - Wang Y
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Leistritz-Edwards, Del
AU  - Leistritz-Edwards D
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Durkin, Melissa R
AU  - Durkin MR
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Tomkins-Tinch, Christopher H
AU  - Tomkins-Tinch CH
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of 
      Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, 
      USA.
FAU - Finkel, Yaara
AU  - Finkel Y
AD  - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, 
      Israel.
FAU - Nachshon, Aharon
AU  - Nachshon A
AD  - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, 
      Israel.
FAU - Gentili, Matteo
AU  - Gentili M
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Rivera, Keith D
AU  - Rivera KD
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Carulli, Isabel P
AU  - Carulli IP
AD  - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, 
      MA, USA.
FAU - Chea, Vipheaviny A
AU  - Chea VA
AD  - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, 
      MA, USA.
FAU - Chandrashekar, Abishek
AU  - Chandrashekar A
AD  - Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 
      Boston, MA, USA.
FAU - Bozkus, Cansu Cimen
AU  - Bozkus CC
AD  - Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount 
      Sinai Hospital, New York, NY, USA.
FAU - Carrington, Mary
AU  - Carrington M
AD  - Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Basic Science 
      Program, Frederick National Laboratory for Cancer Research in the Laboratory of 
      Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA.
CN  - MGH COVID-19 Collection & Processing Team
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Bhardwaj, Nina
AU  - Bhardwaj N
AD  - Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount 
      Sinai Hospital, New York, NY, USA.
FAU - Barouch, Dan H
AU  - Barouch DH
AD  - Harvard Medical School, Boston, MA 02115, USA; Center for Virology and Vaccine 
      Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; Ragon Institute 
      of MGH, MIT and Harvard, Cambridge, MA, USA; Massachusetts Consortium on Pathogen 
      Readiness, Boston, MA, USA.
FAU - Sette, Alessandro
AU  - Sette A
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology (LJI), La Jolla, CA 92037, USA; Department of Medicine, Division of 
      Infectious Diseases and Global Public Health, University of California, San Diego 
      (UCSD), La Jolla, CA 92037, USA.
FAU - Maus, Marcela V
AU  - Maus MV
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; 
      Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 
      02114, USA.
FAU - Rice, Charles M
AU  - Rice CM
AD  - Laboratory of Virology and Infectious Disease, The Rockefeller University, New 
      York, NY 10065, USA.
FAU - Clauser, Karl R
AU  - Clauser KR
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Keskin, Derin B
AU  - Keskin DB
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational 
      Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA; Health 
      Informatics Lab, Metropolitan College, Boston University, Boston, MA, USA; 
      Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - Pregibon, Daniel C
AU  - Pregibon DC
AD  - Repertoire Immune Medicines, Cambridge, MA 02139, USA.
FAU - Hacohen, Nir
AU  - Hacohen N
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of 
      Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Center for 
      Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
FAU - Carr, Steven A
AU  - Carr SA
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Abelin, Jennifer G
AU  - Abelin JG
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
FAU - Saeed, Mohsan
AU  - Saeed M
AD  - Department of Biochemistry, Boston University School of Medicine, Boston, MA, 
      USA; National Emerging Infectious Diseases Laboratories, Boston University, 
      Boston, MA, USA. Electronic address: msaeed1@bu.edu.
FAU - Sabeti, Pardis C
AU  - Sabeti PC
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of 
      Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, 
      USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA; Department 
      of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, 
      Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
LA  - eng
GR  - R01 AI091707/AI/NIAID NIH HHS/United States
GR  - U24 CA210986/CA/NCI NIH HHS/United States
GR  - T32 HG002295/HG/NHGRI NIH HHS/United States
GR  - U19 AI082630/AI/NIAID NIH HHS/United States
GR  - R21 CA216772/CA/NCI NIH HHS/United States
GR  - U24 CA210979/CA/NCI NIH HHS/United States
GR  - U01 CA214125/CA/NCI NIH HHS/United States
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - U19 AI110818/AI/NIAID NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210603
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Peptides)
RN  - 0 (Proteome)
SB  - IM
MH  - A549 Cells
MH  - Alleles
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigen Presentation/immunology
MH  - COVID-19/immunology/virology
MH  - Epitopes, T-Lymphocyte/*immunology
MH  - Female
MH  - HEK293 Cells
MH  - Histocompatibility Antigens Class I/*immunology
MH  - Humans
MH  - Kinetics
MH  - Male
MH  - Mice
MH  - Open Reading Frames/*genetics
MH  - Peptides/chemistry/*immunology
MH  - Proteome/*immunology
MH  - SARS-CoV-2/*immunology
MH  - T-Lymphocytes/immunology
PMC - PMC8173604
OTO - NOTNLM
OT  - HLA Class I
OT  - SARS-CoV-2
OT  - T Cell response
OT  - coronavirus
OT  - immunogenicity
OT  - out-of-frame ORF immunopeptidomics
OT  - viral infection
COIS- Declaration of interests 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 the COVID-19 technology licensing framework to 
      maximize access to university innovations. D.L.-E., C.T., Y.W., M.R.D., W.A.D., 
      and D.C.P. are employees and stockholders of Repertoire Immune Medicines. N.B. is 
      an extramural member of the Parker Institute for Cancer Immunotherapy; receives 
      research funds from Regeneron, Harbor Biomedical, DC Prime, and Dragonfly 
      Therapeutics; and is on the advisory boards of Neon Therapeutics, Novartis, 
      Avidea, Boehringer Ingelheim, Rome Therapeutics, Roswell Park Comprehensive 
      Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, 
      Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. 
      A.S. is a consultant for Gritstone, Flow Pharma, CellCarta, OxfordImmunotech, 
      Immunoscape, and Avalia. La Jolla Institute for Immunology has filed for patent 
      protection for various aspects of T cell epitope and vaccine design work. 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 a project unrelated 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 a non-executive board member and 
      shareholder of Danaher Corporation.
FIR - Lavin-Parsons, Kendall
IR  - Lavin-Parsons K
FIR - Parry, Blair
IR  - Parry B
FIR - Lilley, Brendan
IR  - Lilley B
FIR - Lodenstein, Carl
IR  - Lodenstein C
FIR - McKaig, Brenna
IR  - McKaig B
FIR - Charland, Nicole
IR  - Charland N
FIR - Khanna, Hargun
IR  - Khanna H
FIR - Margolin, Justin
IR  - Margolin J
FIR - Gonye, Anna
IR  - Gonye A
FIR - Gushterova, Irena
IR  - Gushterova I
FIR - Lasalle, Tom
IR  - Lasalle T
FIR - Sharma, Nihaarika
IR  - Sharma N
FIR - Russo, Brian C
IR  - Russo BC
FIR - Rojas-Lopez, Maricarmen
IR  - Rojas-Lopez M
FIR - Sade-Feldman, Moshe
IR  - Sade-Feldman M
FIR - Manakongtreecheep, Kasidet
IR  - Manakongtreecheep K
FIR - Tantivit, Jessica
IR  - Tantivit J
FIR - Fisher Thomas, Molly
IR  - Fisher Thomas M
EDAT- 2021/06/26 06:00
MHDA- 2021/08/04 06:00
PMCR- 2021/06/03
CRDT- 2021/06/25 20:11
PHST- 2020/10/12 00:00 [received]
PHST- 2021/04/21 00:00 [revised]
PHST- 2021/05/27 00:00 [accepted]
PHST- 2021/06/26 06:00 [pubmed]
PHST- 2021/08/04 06:00 [medline]
PHST- 2021/06/25 20:11 [entrez]
PHST- 2021/06/03 00:00 [pmc-release]
AID - S0092-8674(21)00701-7 [pii]
AID - 10.1016/j.cell.2021.05.046 [doi]
PST - ppublish
SO  - Cell. 2021 Jul 22;184(15):3962-3980.e17. doi: 10.1016/j.cell.2021.05.046. Epub 
      2021 Jun 3.