Human leukocyte antigen susceptibility map for SARS-CoV-2

Austin Nguyen; Julianne K David; Sean K Maden; Mary A Wood; Benjamin R Weeder; Abhinav Nellore; Reid F Thompson

To assess the potential for cross-protective immunity conferred by prior exposure to common human coronaviruses (i.e. HKU1, OC43, NL63, and 229E), we next sought to characterize the conservation of the SARS-CoV-2 proteome across diverse coronavirus subgenera to identify highly conserved linear epitopes. After aligning reference proteome sequence data for 5 essential viral components (ORF1ab, S, E, M, and N proteins) across 34 distinct alpha-and betacoronaviruses , including all known human coronaviruses, we identified 48 highly conserved amino acid sequence spans (Appendix 1). Acknowledging the challenges inferring cross-protective immunity among closely related peptides, we confined attention exclusively to identical peptide matches. Among conserved sequences, 44 SARS-CoV-2 sequences would each be anticipated to generate at least one 8-to 12-mer linear peptide epitope also present within at least one other common human coronavirus (Supplementary Table S2, Figure 2 ). In total, 564 such 8-to 12-mer peptides were found to share 100% identity with corresponding OC43, HKU1, NL63, and 229E sequences (467, 460, 179, and 157 peptides, respectively) (Supplementary Table S3 ). For the subset of these potentially cross-protective peptides that are anticipated to be generated via the MHC class I antigen processing pathway, we performed binding affinity predictions across 145 different HLA-A, -B, and -C alleles. As above, we demonstrate the SARS-CoV-2-specific distribution of per-allele presentation for these conserved peptides. We found that alleles HLA-A*02:02, HLA-B*15:03, and HLA-C*12:03 were the top presenters of conserved peptides. Conversely, we note that 56 different HLA alleles demonstrated no appreciable binding affinity (<500nM) to any of the conserved SARS-CoV-2 peptides, suggesting a concomitant lack of potential for cross-protective immunity from other human coronaviruses. We note, in particular, HLA-B*46:01 is among these alleles. Note also that the putative capacity for conserved peptide presentation is unrelated to the HLA allelic frequency in the population ( Figure 3 ). Moreover, we see no appreciable global correlation between conservation of the SARS-CoV-2 proteome and its predicted MHC binding affinity, suggesting a lack of selective pressure for or against the capacity to present coronavirus epitopes (p=0.27 [Fisher's exact test], Supplementary Figure S2 ).