The impact of SARS-CoV-2 spike mutation on peptide presentation is HLA allomorph-specific

You Min Ahn; Janesha C Maddumage; Emma J Grant; Demetra S M Chatzileontiadou; W W J Gihan Perera; Brian M Baker; Christopher Szeto; Stephanie Gras

doi:10.1016/j.crstbi.2024.100148

The impact of SARS-CoV-2 spike mutation on peptide presentation is HLA allomorph-specific

Curr Res Struct Biol. 2024 Apr 29:7:100148. doi: 10.1016/j.crstbi.2024.100148. eCollection 2024.

Authors

You Min Ahn^{1

2}, Janesha C Maddumage^{1

2}, Emma J Grant^{1

2

3}, Demetra S M Chatzileontiadou^{1

2

3}, W W J Gihan Perera⁴, Brian M Baker⁴, Christopher Szeto^{1

2

5}, Stephanie Gras^{1

2

3}

Affiliations

¹ Infection & Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, Victoria, Australia.
² Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Agriculture (SABE), La Trobe University, Bundoora, Victoria, Australia.
³ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
⁴ Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
⁵ Australian Synchrotron, ANSTO, Clayton, Victoria, Australia.

Abstract

CD8⁺ T cells are crucial for viral elimination and recovery from viral infection. Nonetheless, the current understanding of the T cell response to SARS-CoV-2 at the antigen level remains limited. The Spike protein is an external structural protein that is prone to mutations, threatening the efficacy of current vaccines. Therefore, we have characterised the immune response towards the immunogenic Spike-derived peptide (S_976-984, VLNDILSRL), restricted to the HLA-A*02:01 molecule, which is mutated in both Alpha (S982A) and Omicron BA.1 (L981F) variants of concern. We determined that the mutation in the Alpha variant (S982A) impacted both the stability and conformation of the peptide, bound to HLA-A*02:01, in comparison to the original S_976-984. We identified a longer and overlapping immunogenic peptide (S_975-984, SVLNDILSRL) that could be presented by HLA-A*02:01, HLA-A*11:01 and HLA-B*13:01 allomorphs. We showed that S975-specific CD8⁺ T cells were weakly cross-reactive to the mutant peptides despite their similar conformations when presented by HLA-A*11:01. Altogether, our results show that the impact of SARS-CoV-2 mutations on peptide presentation is HLA allomorph-specific, and that post vaccination there are T cells able to react and cross-react towards the variant of concern peptides.

Keywords: HLA; SARS-CoV-2; T cells; Viral epitopes; Viral mutation; X-ray crystallography.

Grants and funding

R35 GM118166/GM/NIGMS NIH HHS/United States