Mutational pressure promotes release of proteasome-generated public CD8+ T cell epitopes from SARS-CoV-2 RBD of Omicron and its current lineages

The COVID-19 pandemic was the most dramatic in the newest history with nearly 7 million deaths and global impact on mankind. Here, we report binding index of 305 human leukocyte antigen (HLA) class I molecules from 18,771 unique haplotypes of 28,104 individuals to 821 peptides experimentally observed from spike protein receptor binding domain (RBD) of five main SARS-CoV-2 strains hydrolyzed by human proteasomes with constitutive and immune catalytic phenotypes. Our data read that mutations in the human angiotensin-converting enzyme 2 (hACE2)-binding region RBD496-513 of Omicron B.1.1.529 strain results in a dramatic increase of proteasome-mediated release of two public HLA class I epitopes. Global population analysis of HLA class I haplotypes, specific to these peptides, demonstrated decreased mortality of human populations enriched in these haplotypes from COVID-19 after but not before December, 2021, when Omicron became dominant SARS-CoV-2 strain. Noteworthy, currently circulating BA.2.86 and JN.1 strains contain same amino acid substitutions at key proteasomal cleavage sites, thus preserving identified core epitopes. [Display omitted] •Mutations in SARS-CoV-2 Omicron lead to altered proteasome-mediated RBD processing•Release of public CD8 T cell epitopes by proteasome is elevated in Omicron RBD•Human HLA class I alleles providing increased resistance to Omicron are identified•Currently circulating SARS-CoV-2 lineages preserve identified core epitope Immunology; Immune response; Cell biology