tetano
Editor, Senior Moderator
Nat Commun
. 2025 Nov 19;16(1):10156.
doi: 10.1038/s41467-025-65251-8. C > U mutations generate immunogenic peptides in SARS-CoV-2
Gergő Mihály Balogh[SUP] 1 2 3 [/SUP], Balázs Koncz[SUP] 4 5 [/SUP], Leó Asztalos[SUP] 6 [/SUP], Eszter Ari[SUP] 4 7 8 9 [/SUP], Nikolett Gémes[SUP] 10 [/SUP], Gábor J Szebeni[SUP] 10 11 [/SUP], Benjamin Tamás Papp[SUP] 4 5 6 [/SUP], Franciska Tóth[SUP] 4 5 12 [/SUP], Balázs Papp[SUP] 4 7 9 13 [/SUP], Csaba Pál[SUP] 14 [/SUP], Máté Manczinger[SUP] 15 16 17 [/SUP]
Affiliations
The rapid spread of SARS-CoV-2 worldwide has given rise to numerous variants. While the impact of viral mutations on antibody escape has been extensively studied, an unresolved issue concerns how emerging mutations shape HLA-restricted T-cell immune responses. Here, we analyse SARS-CoV-2 genomic variants, showing that 27% of the mutations are C > U transitions, a phenomenon common in human RNA viruses and primarily attributed to APOBEC3 enzyme-driven mutagenesis. We find that this mutation bias generally enhances viral peptide binding to human leukocyte antigen class I (HLA-I) molecules, producing immunogenic epitopes that trigger cytotoxic adaptive immune responses in most individuals across diverse populations. We also identify several HLA-I variants that are especially well-suited for presenting viral epitopes generated by these mutations. Intriguingly, individuals carrying these specific alleles are predominantly located in South and East Asia. Finally, we show that carrying HLA-I molecules that are less likely to bind C > U-induced viral peptides increases risk for severe COVID-19 disease. Our work suggests a link between C > U hypermutation and HLA-I-based presentation of viral epitopes, which may reflect the evolutionary outcome of ancient RNA virus pandemics. More broadly, our findings imply that SARS-CoV-2 diversification leads to ongoing gains of T-cell epitopes despite natural selection favouring immune escape.
. 2025 Nov 19;16(1):10156.
doi: 10.1038/s41467-025-65251-8. C > U mutations generate immunogenic peptides in SARS-CoV-2
Gergő Mihály Balogh[SUP] 1 2 3 [/SUP], Balázs Koncz[SUP] 4 5 [/SUP], Leó Asztalos[SUP] 6 [/SUP], Eszter Ari[SUP] 4 7 8 9 [/SUP], Nikolett Gémes[SUP] 10 [/SUP], Gábor J Szebeni[SUP] 10 11 [/SUP], Benjamin Tamás Papp[SUP] 4 5 6 [/SUP], Franciska Tóth[SUP] 4 5 12 [/SUP], Balázs Papp[SUP] 4 7 9 13 [/SUP], Csaba Pál[SUP] 14 [/SUP], Máté Manczinger[SUP] 15 16 17 [/SUP]
Affiliations
- PMID: 41258064
- PMCID: PMC12630872
- DOI: 10.1038/s41467-025-65251-8
The rapid spread of SARS-CoV-2 worldwide has given rise to numerous variants. While the impact of viral mutations on antibody escape has been extensively studied, an unresolved issue concerns how emerging mutations shape HLA-restricted T-cell immune responses. Here, we analyse SARS-CoV-2 genomic variants, showing that 27% of the mutations are C > U transitions, a phenomenon common in human RNA viruses and primarily attributed to APOBEC3 enzyme-driven mutagenesis. We find that this mutation bias generally enhances viral peptide binding to human leukocyte antigen class I (HLA-I) molecules, producing immunogenic epitopes that trigger cytotoxic adaptive immune responses in most individuals across diverse populations. We also identify several HLA-I variants that are especially well-suited for presenting viral epitopes generated by these mutations. Intriguingly, individuals carrying these specific alleles are predominantly located in South and East Asia. Finally, we show that carrying HLA-I molecules that are less likely to bind C > U-induced viral peptides increases risk for severe COVID-19 disease. Our work suggests a link between C > U hypermutation and HLA-I-based presentation of viral epitopes, which may reflect the evolutionary outcome of ancient RNA virus pandemics. More broadly, our findings imply that SARS-CoV-2 diversification leads to ongoing gains of T-cell epitopes despite natural selection favouring immune escape.