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

Agerer, Benedikt; Koblischke, Maximilian; Gudipati, Venugopal; Montaño-Gutierrez, Luis Fernando; Smyth, Mark J.; Popa, Alexandra; Genger, Jakob-Wendelin; Endler, Lukas; Florian, David M.; Mühlgrabner, Vanessa; Graninger, Marianne; Aberle, Stephan W.; Husa, Anna-Maria; Shaw, Lisa E.; Lercher, Alexander; Gattinger, Pia; Torralba-Gombau, Ricard; Trapin, Doris; Penz, Thomas; Barreca, Daniele; Faé, Ingrid; Wenda, S.; Traugott, Marianna; Walder, Gernot; Pickl, Winfried F.; Thiel, Volker; Allerberger, Franz; Stockinger, Hannes; Puchhammer‐Stöckl, Elisabeth; Weninger, Wolfgang; Fischer, Gottfried; Hoepler, Wolfgang; Pawelka, Erich; Zoufaly, Alexander; Valenta, Rudolf; Bock, Christoph; Paster, Wolfgang; Geyeregger, René; Farlik, Matthias; Halbritter, Florian; Huppa, Johannes B.; Aberle, Judith H.; Bergthaler, Andréas

doi:10.1126/sciimmunol.abg6461

Cited by 155 publications

(185 citation statements)

References 70 publications

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“…Moreover, our global analysis validated the presence of two previously reported CD8+ T cell mutated epitopes (i.e. GLMWLSYFI à GFMWLSYFI, found in 38 genomes; and MEVTPSGTWL à MKVTPSGTWL, found in 23 genomes), which were shown to lose binding to HLA-A*02:01 and -B*40:01, respectively, in addition to disrupt epitope-specific CD8+ T cell response in COVID-19 patients (Figure S3) (Agerer et al, 2021). Together, these results demonstrate that mutations driving the global genomic diversity of SARS-CoV-2 can drastically disrupt HLA binding of clinically relevant CD8+ T cell epitopes, including epitopes encoded by the immunodominant S and N antigens, therefore affecting epitope-specific T cell responses in COVID-19 patients.…”

Section: The Global Diversity Of Sars-cov-2 Genomes Influences the Repertoire Of T Cell Targetssupporting

confidence: 82%

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Hamelin

Fournelle

Grenier

et al. 2021

Preprint

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The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

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Section: The Global Diversity Of Sars-cov-2 Genomes Influences the Repertoire Of T Cell Targetssupporting

confidence: 82%

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Hamelin

Fournelle

Grenier

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…In addition, it remains to be elucidated whether pre-existing memory T cells that are cross-reactive to SARS-CoV-2 play a protective or detrimental role in patients with COVID-19. SARS-CoV-2 mutations that abrogate binding to MHC have been reported (Agerer et al, 2021), a recent study reported insignificant impacts of variants on SARS-CoV-2-specific CD4 + and CD8 + T-cell responses (Tarke et al, 2021). Most T-cell epitopes were conserved among emerging SARS-CoV-2 variants.…”

Section: T-cell Responses Elicited By Covid-19 Vaccinesmentioning

confidence: 96%

Phenotypes and Functions of SARS-CoV-2-Reactive T Cells

Jung

Shin

2021

Molecules and Cells

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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is an ongoing pandemic disease. SARS-CoV-2specific CD4 + and CD8 + T-cell responses have been detected and characterized not only in COVID-19 patients and convalescents, but also unexposed individuals. Here, we review the phenotypes and functions of SARS-CoV-2-specific T cells in COVID-19 patients and the relationships between SARS-CoV-2-specific T-cell responses and COVID-19 severity. In addition, we describe the phenotypes and functions of SARS-CoV-2-specific memory T cells after recovery from COVID-19 and discuss the presence of SARS-CoV-2-reactive T cells in unexposed individuals and SARS-CoV-2-specific T-cell responses elicited by COVID-19 vaccines. A better understanding of T-cell responses is important for effective control of the current COVID-19 pandemic.

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“…To experimentally assess the impact of the identified nonsynonymous mutations on peptide binding to MHCI, we performed differential scanning fluorimetry (DSF) ( 38 , 40 ). Briefly, we performed UV-mediated peptide-exchange reactions with H2-D b -UVCP (ultraviolet light-cleavable peptide) complexes in the presence of WT or the mutant peptides.…”

Section: Resultsmentioning

confidence: 99%

“…The UV-cleavable peptides for H2-D b and H2-K b , ASNENJETM ( 36 ) and FAPGNYJAL ( 39 ) respectively, were purchased crude (70% purity) from Intavis Peptide Services and were used in all differential scanning fluorimetry experiments. The peptide-MHCI complexes for the differential scanning fluorimetry experiments were made ( 37 ) and the experiments performed as described previously ( 40 ). The GP33-41 peptides used in Figures 3D, E were the same as for the intracellular cytokine experiment (see above).…”

Section: Methodsmentioning

confidence: 99%

Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus

et al. 2021

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Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections.

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

Cited by 155 publications

References 70 publications

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Phenotypes and Functions of SARS-CoV-2-Reactive T Cells

Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus

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

Cited by 155 publications

References 70 publications

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Phenotypes and Functions of SARS-CoV-2-Reactive T Cells

Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus

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