Dataset Information

SARS-CoV-2 escapes CD8 T cell surveillance via mutations in MHC-I restricted epitopes [10x]

ABSTRACT: CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified non-synonymous mutations in MHC-I restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding, which was associated with a loss of recognition and functional responses by CD8+ T cells isolated from HLA-matched COVID-19 patients. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through sporadically emerging escape mutations in MHC- I restricted viral epitopes.

PROVIDER: EGAS00001005060 | EGA |

REPOSITORIES: EGA

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SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses.

Agerer Benedikt B Koblischke Maximilian M Gudipati Venugopal V Montaño-Gutierrez Luis Fernando LF Smyth Mark M Popa Alexandra A Genger Jakob-Wendelin JW Endler Lukas L Florian David M DM Mühlgrabner Vanessa V Graninger Marianne M Aberle Stephan W SW Husa Anna-Maria AM Shaw Lisa Ellen LE Lercher Alexander A Gattinger Pia P Torralba-Gombau Ricard R Trapin Doris D Penz Thomas T Barreca Daniele D Fae Ingrid I Wenda Sabine S Traugott Marianna M Walder Gernot G Pickl Winfried F WF Thiel Volker V Allerberger Franz F Stockinger Hannes H Puchhammer-Stöckl Elisabeth E Weninger Wolfgang W Fischer Gottfried G Hoepler Wolfgang W Pawelka Erich E Zoufaly Alexander A Valenta Rudolf R Bock Christoph C Paster Wolfgang W Geyeregger René R Farlik Matthias M Halbritter Florian F Huppa Johannes B JB Aberle Judith H JH Bergthaler Andreas A

Science immunology 20210301 57

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T ...[more]

PMID: 33664060

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Project description:Next-generation T-cell-directed vaccines for COVID-19 aim to induce durable T-cell immunity against circulating and future hypermutated SARS-CoV-2 variants. Mass Spectrometry (MS)based immunopeptidomics holds promise for guiding vaccine design, but computational challenges impede the precise and unbiased identification of conserved T-cell epitopes crucial for vaccines against rapidly mutating viruses. We introduce a computational framework and analysis platform integrating a novel machine learning algorithm, immunopeptidomics, intra-host data, epitope immunogenicity, and geo-temporal CD8+ T-cell epitope conservation analyses. Central to our approach is MHCvalidator, a novel artificial neural network algorithm enhancing MS-based immunopeptidomics sensitivity by modeling antigen presentation and sequence features. MHCvalidator identified a novel nonconventional SARS-CoV-2 T-cell epitope presented by B7 supertype molecules, originating from a +1-frameshift in a truncated Spike (S) antigen, supported by ribo-seq data. Intra-host analysis of SARS-CoV-2 proteomes from ~100,000 COVID-19 patients revealed a prevalent S antigen truncation in ~51% of cases, exposing a rich source of frameshifted viral antigens. Our framework includes EpiTrack, a new computational pipeline tracking global mutational dynamics of MHCvalidator-identified SARS-CoV-2 CD8+ epitopes from vaccine BNT162b4. While most vaccine-encoded CD8+ epitopes exhibit global conservation from January 2020 to October 2023, a highly immunodominant A*01-associated epitope, especially in hospitalized patients, undergoes substantial mutations in Delta and Omicron variants. Our approach unveils unprecedented SARS-CoV-2 T-cell epitopes, elucidates novel antigenic features, and underscores mutational dynamics of vaccine-relevant epitopes. The analysis platform is applicable to any viruses, and underscores the need for continual vigilance in T-cell vaccine development against the evolving landscape of hypermutating SARS-CoV-2 variants.

Dataset Information

SARS-CoV-2 escapes CD8 T cell surveillance via mutations in MHC-I restricted epitopes [10x]

Publications

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8<sup>+</sup> T cell responses.

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