C > U mutations generate immunogenic peptides in SARS-CoV-2

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• SARS-CoV-2 variants pose global health challenges.
• Understanding mutations' impact on T-cell immunity is crucial.
• APOBEC3 enzyme-driven C>U transitions are common in RNA viruses.

Purpose of the Study:

• To investigate how SARS-CoV-2 mutations influence HLA-restricted T-cell responses.
• To analyze the role of C>U transitions in viral peptide presentation.
• To explore the association between HLA-I variants, C>U mutations, and COVID-19 severity.

Main Methods:

• Genomic analysis of SARS-CoV-2 variants.
• Assessment of viral peptide binding to HLA-I molecules.
• Correlation analysis between HLA-I alleles and COVID-19 outcomes.

Main Results:

• 27% of SARS-CoV-2 mutations are C>U transitions, driven by APOBEC3.
• C>U mutations enhance viral peptide binding to HLA-I, generating immunogenic epitopes.
• Specific HLA-I variants, prevalent in Asia, are adept at presenting these epitopes.
• Reduced binding of C>U-induced peptides to certain HLA-I molecules correlates with severe COVID-19.

Conclusions:

• A link exists between C>U hypermutation and HLA-I-mediated T-cell epitope presentation.
• This interaction may reflect evolutionary adaptations to past pandemics.
• SARS-CoV-2 diversification generates T-cell epitopes, potentially counteracting immune escape.