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

The rapid, global dispersion of SARS-CoV-2 has led to the emergence of a diverse range of variants. Here, we describe 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. We analyzed a total of 330,246 high-quality SARS-CoV-2 genome assemblies, sampled across 143 countries and all major continents from December 2019 to December 2020 before mass vaccination or the rise of the Delta variant. 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; this 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. [Display omitted] •Link between SARS-COV-2 mutation biases, HLA alleles, and immune escape•Dominant C→U SARS-CoV-2 mutations diversify the CD8+ T cell epitope repertoire•Mutation biases modulate epitope presentation in an HLA-supertype-dependent manner•Preferential loss of epitopes in B7 HLA supertype due to prevalent loss of proline Hamelin et al. investigated the global mutation landscape of SARS-CoV-2 by interrogating 330,246 SARS-CoV-2 sequences from GISAID. The dominant C→U mutation type was found to diversify the repertoire of experimentally validated SARS-CoV-2 CD8+ T cell epitopes in an HLA-supertype-dependent manner. Notably, the prevalent removal of proline was predicted to preferentially abrogate epitopes presented by the B7 HLA supertype. This model lays a foundation for testing the impact of SARS-COV-2 mutants on T cell escape in an HLA-dependent manner.