Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

Abstract

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

Keywords: COVID-19; HLA; MHC class I; SARS-CoV-2; coronavirus.

FIG 1

Distribution of HLA allelic presentation of 8- to 12-mers from the SARS-CoV-2 proteome. At right, the number of peptides (see Table S1) that putatively bind to each of 145 HLA alleles is shown as a series of horizontal bars, with dark and light shading indicating the number of tightly (<50 nM) and loosely (<500 nM) binding peptides, respectively, and with green, orange, and purple representing HLA-A, -B, and -C alleles, respectively. Alleles are sorted in descending order based on the number of peptides that they bind (<500 nM). The corresponding estimated allelic frequency in the global population is also shown (left), with the length of each horizontal bar indicating absolute frequency in the population.

FIG 2

Amino acid sequence conservation of four linear peptide example sequences from three human coronavirus proteins. Protein sequence alignments are shown for nucleocapsid (N), membrane (M), and ORF1ab polyprotein (helicase) across all five known human betacoronaviruses (SARS-CoV-2, SARS-CoV, HKU1, OC43, and MERS-CoV) and two known human alphacoronaviruses (229E and NL63). Each row in the three depicted sequence alignments corresponds to the protein sequence from the indicated coronavirus, with the starting coordinate of the viral protein sequence shown at left and position coordinates of the overall alignment displayed above. Blue shading indicates the extent of sequence identity, with the darkest blue shading indicating a 100% match for that amino acid across all sequences. The four red-highlighted sequences correspond to highly conserved peptides ≥8 amino acids in length (PRWYFYYLGTGP, WSFNPETN, QPPGTGKSH, and VYTACSHAAVDALCEKA, see Table S2).

FIG 3

Distribution of HLA allelic presentations of highly conserved human coronavirus peptides with potential to elicit cross-protective immunity to COVID-19. At right, the number of conserved peptides (see Table S3) that putatively bind to a subset of 89 HLA alleles is shown as a series of horizontal bars, with dark and light shading indicating the number of tightly (<50 nM) and loosely (<500 nM) binding peptides, respectively, and with green, orange, and purple representing HLA-A, -B, and -C alleles, respectively. Alleles are sorted in descending order based on the number of peptides they are anticipated to present (binding affinity, <500 nM). The corresponding allelic frequency in the global population is also shown (left), with the length of each horizontal bar indicating absolute frequency in the population.

FIG 4

Distribution of allelic presentation of conserved 8- to 12-mers across the entire SARS-CoV-2 proteome for all HLA alleles and individually for HLA-A, HLA-B, and HLA-C (first, second, third, and fourth plots from top, respectively) with dark and light shading indicating the number of tightly (<50 nM) and loosely (<500 nM) binding peptides, respectively. Positions are derived from a concatenation of coding sequences (CDSs) as indicated in the bottom panel. Tightly binding peptides are confined to ORF1ab. The sequence begins with only the last 12 amino acids of ORF1a because all but the last four amino acids of ORF1a are contained in ORF1ab, and we considered binding peptides up to 12 amino acids (AA) in length.

FIG 5

Global HLA allele frequency distribution heat maps for six HLA-A, -B, and -C alleles. The leftmost panels show the global allele frequency distributions by country for three representative alleles (HLA-A*02:02, HLA-B*15:03, and HLA-C*12:03) with the predicted capacities to present the greatest repertoire of epitopes from the SARS-CoV-2 proteome (21.1%, 19.1%, and 7.9% of presentable epitopes, respectively). The rightmost panels show the global allele frequency distributions by country for three representative alleles (HLA-A*25:01, HLA-B*46:01, and HLA-C*01:02) with the lowest predicted levels epitope presentation from the SARS-CoV-2 proteome (0.2%, 0%, and 0% of presentable epitopes, respectively). Heat map coloring corresponds to the individual HLA allele frequency within each country, ranging from lowest (white/yellow) to highest (red) frequency as indicated in the legend below each map.

FIG 6

Distributions of SARS-CoV-2 peptide presentation across HLA haplotypes. The leftmost panels show the distributions of SARS-CoV-2 peptide presentation capacity for haplotypes containing one of three representative HLA alleles (HLA-A*02:02, HLA-B*15:03, and HLA-C*12:03) with the greatest predicted repertoire of epitopes from the SARS-CoV-2 proteome. The rightmost panels show the distributions of SARS-CoV-2 peptide presentation capacity for haplotypes containing one of three representative alleles (HLA-A*25:01, HLA-B*46:01, and HLA-C*01:02) with the lowest predicted levels of epitope presentation from the SARS-CoV-2 proteome. Black and gray bars represent full and partial haplotypes, respectively. Blue and red dashed lines represent the percentages of presented SARS-CoV-2 peptides for the indicated allele itself (blue) and its global population frequency weighted average presentation across its observed haplotypes (red).