Balogh, Gergő Mihály and Koncz, Balázs and Asztalos, Leó and Ari, Eszter and Gémes, Nikolett and Szebeni, Gábor and Papp, Benjamin Tamás and Tóth, Franciska and Papp, Balázs and Pál, Csaba and Manczinger, Máté (2025) C > U mutations generate immunogenic peptides in SARS-CoV-2. NATURE COMMUNICATIONS, 16 (1). No. 10156. ISSN 2041-1723
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Abstract
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.
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| Additional Information: | Funding Agency and Grant Number: European Union [739593]; European Union's Horizon Europe research and innovation program [101136582]; European Research Council [ERC-2023-ADG 101142626]; National Research Development and Innovation Office [K 146323, 2022-2.1.1-NL-2022-00008, FK-142312, PD-146654, FK22-142877, 2023-1.1.1-PIACI_FOKUSZ-2024-00036]; National Research, Development, and Innovation Office (NKFI), Hungary; National Academy of Scientist Education; Hungarian Ministry of Innovation and Technology [FEIF/646-4/2021-ITM_SZERZ, TKCS-2024/66, RRF-2.3.1-21-2022-00006, NKP-22-4, NKP-23-4, NKP-23-5]; New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund [C1764415]; Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund; Bolyai Jnos Research Fellowship [BO/00582/22/8]; Hungarian Academy of Sciences [44917] Funding text: The work was supported by the European Union's Horizon 2020 research and innovation program grant No. 739593 (M.M., B.K, G.M.B, and B.P); the European Union's Horizon Europe research and innovation program under grant agreement No 101136582 Acronym ID-DarkMatter-NCD (M.M.); the European Research Council ERC-2023-ADG 101142626 FutureAntibiotics (C.P.); the National Research Development and Innovation Office K 146323 (C.P.); the National Laboratory of Biotechnology Grant 2022-2.1.1-NL-2022-00008 (C.P.); the Hungarian Scientific Research Fund grant FK-142312 (M.M.), PD-146654 (B.K.), FK22-142877 (G.J.S.) and 2023-1.1.1-PIACI_FOKUSZ-2024-00036 (G.J.S.) from the National Research, Development, and Innovation Office (NKFI), Hungary; the National Academy of Scientist Education under the sponsorship of the Hungarian Ministry of Innovation and Technology (FEIF/646-4/2021-ITM_SZERZ), the HUN-REN (TKCS-2024/66; to B.P. and E.A.) and the National Laboratory for Health Security grant RRF-2.3.1-21-2022-00006 (B.P.). G.M.B. was supported by the UNKP-22-4 and UNKP-23-4, M.M., B.K., and G.J.S. were supported by the UNKP-23-5 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. N.G. was supported by the KDP-2021 Program (C1764415) of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. M.M., B.K. and G.J.S. were supported by the Bolyai Janos Research Fellowship (BO/00582/22/8) of the Hungarian Academy of Sciences. COVID-19 outcome analysis was performed using data from the UK Biobank Resource under application number 44917. |
| Subjects: | Q Science / természettudomány > QR Microbiology / mikrobiológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 08 Feb 2026 14:02 |
| Last Modified: | 08 Feb 2026 14:02 |
| URI: | https://real.mtak.hu/id/eprint/233503 |
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