Natural heteroclitic-like peptides are generated by SARS-CoV-2 mutations

• Published in: bioRxiv 2022-10
• Main Authors: Tiezzi, Camilla, Vecchi, Andrea, Rossi, Marzia, Cavazzini, Davide, Bolchi, Angelo, Laccabue, Diletta, Sacchelli, Luca, Brillo, Federica, Meschi, Tiziana, Ticinesi, Andrea, Nouvenne, Antonio, Donofrio, Gaetano, Zanelli, Paola, Benecchi, Magda, Giuliodori, Silvia, Fisicaro, Paola, Montali, Ilaria, Urbani, Simona, Pedrazzi, Giuseppe, Missale, Gabriele, Telenti, Amalio, Corti, Davide, Ottonello, Simone, Ferrari, Carlo, Boni, Carolina
• Format: Article
• Language: English
• Subjects: Biotechnology; CD8 antigen; Epitopes; Humoral immunity; Lymphocytes; Lymphocytes T; Mutation; Peptides; Severe acute respiratory syndrome coronavirus 2; Spike protein
• DOI: 10.1101/2022.10.28.513849

Mutations carried by SARS-CoV-2 spike protein variants may promote viral escape from immune protection. Humoral immunity is sensitive to evasion by SARS-CoV-2 mutants, but the impact of viral evolution on the interplay between virus and host CD8 T cell reactivity remains uncertain. By a systematic functional analysis of 30 spike variant mutations, we show that in vaccinated as well as convalescent subjects, mutated epitopes can have not only a neutral or abrogating effect on the recognition by CD8 T cells but can also enhance or even generate de novo CD8 T cell responses. Large pools of peptides spanning the entire spike sequence and comprising previously identified CD8 T cell epitopes were then used in parallel with variant peptides to define strength and multispecificity of total anti-spike CD8 responses. In some individuals, CD8 cells were narrowly focused on a few epitopes indicating that in this context of weak and oligospecific responses the overall antiviral protection can likely benefit of the function enhancing effect of heteroclitic-like mutations. In conclusion, appearance of mutated stimulatory epitopes likely reflects an epiphenomenon of SARS-CoV-2 evolution driven by antibody evasion and increased transmissibility, that might bear clinical relevance in a subset of individuals with weak and oligospecific CD8 T cell responses. Competing Interest Statement A.T. and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.F.: Grant: Gilead, Abbvie. Consultant: Gilead, Abbvie, Vir Biotechnology Inc, Arrowhead, Transgene, BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Footnotes * Missing Figure 1 added.