CD8 T cell epitope generation toward the continually mutating SARS-CoV-2 spike protein in genetically diverse human population: Implications for disease control and prevention

Abstract

The ongoing pandemic of SARS-CoV-2 has brought tremendous crisis on global health care systems and industrial operations that dramatically affect the economic and social life of numerous individuals worldwide. Understanding anti-SARS-CoV-2 immune responses in population with different genetic backgrounds and tracking the viral evolution are crucial for successful vaccine design. In this study, we reported the generation of CD8 T cell epitopes by a total of 80 alleles of three major class I HLAs using NetMHC 4.0 algorithm for the spike protein of SARS-CoV-2, a key antigen that is targeted by both B cells and T cells. We found diverse capacities of S protein specific epitope presentation by different HLA alleles with very limited number of predicted epitopes for HLA-B*2705, HLA-B*4402 and HLA-B*4403 and as high as 132 epitopes for HLA-A*6601. Our analysis of 1000 S protein sequences from field isolates collected globally over the past few months identified three recurrent point mutations including L5F, D614G and G1124V. Differential effects of these mutations on CD8 T cell epitope generation by corresponding HLA alleles were observed. Finally, our multiple alignment analysis indicated the absence of seasonal CoV induced cross-reactive CD8 T cells to drive these mutations. Our findings provided molecular explanations for the observation that individuals with certain HLA alleles such as B*44 are more prone to SARS-CoV-2 infection. Studying anti-S protein specific CD8 T cell immunity in diverse genetic background is critical for better control and prevention of the SARS-CoV-2 pandemic.

Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates

“…They also may change the solvent-accessible area and thus antibody binding when they involve surface residues of the trimeric spike protein complex as shown for the 20 most frequent solvent-accessible mutations. While we had no information on the HLA-restriction of the published T-cell epitopes, the influence on CD8+ T cell epitope generation by different HLA alleles was investigated for the three common mutations L5F, D614G and G1124V (44). These mutations were predicted to result in epitope gains, losses or higher or lower HLA binding affinities.…”

Immunodominance complexity: lessons yet to be learned from dominant T cell responses to SARS-COV-2

“…Immunogenic peptides from S, M, N and ORF protein have been reported to be able to activate CD8 + T cells [ 1 • , 2 • , 3 • , 4 , 5 • ] (reviewed in [ 6 • ]). Several HLA-A•02 restricted CD8 epitope variants within S protein were correlated with infection susceptibility and severity [ 7 ]. T cell responses against structural and accessory proteins have been identified in ∼70% of acute and convalescent patients [ 2 • ].…”

Molecular characterization of SARS-CoV-2 from Bangladesh: implications in genetic diversity, possible origin of the virus, and functional significance of the mutations

“…Associated with higher mutation rate ( Pachetti et al., 2020 ) 15324C>T Synonymous ORF1ab None 8 - - - - - 15738C>T Synonymous ORF1ab None 7 - - - - - 18877C>T Synonymous ORF1ab None 24 - - - - Associated with mutation density in M and E gene ( Eskier et al., 2020a ) 19723G>T Missense ORF1ab V6487F 17 Decrease -1.55 Tolerated - - 21575C>T Missense S L5F 8 Decrease -0.98 Tolerated - May increase hydrophobicity of the signal peptide thus facilitate in viral secretion from cell ( Zhan et al., 2020 ) hence increase infectivity ( Li et al., 2020 ). It also increases epitope binding affinity ( Guo and Guo, 2020 ) 21855C>T Missense S S98F 6 Neutral 0.00 Tolerated - 22444C>T Synonymous S None 24 - - - - Found to co-evolve with 28854C>T and unique to Indian isolates ( Banerjee et al., 2020 ) 23403A>G Missense S D614G 315 Decrease -0.93 ...…”