DISCUSSION
To the best of our knowledge, this was the first study to evaluate per-allele viral proteome presentation across a wide range of HLA alleles using MHC-peptide binding affinity predictors. This report also introduces the relationship between coronavirus sequence conservation and MHC class I antigen presentation. We show that individual HLA, haplotype, and full-genotype variability likely influence the capacity to respond to SARS-CoV-2 infection, and we note certain alleles in particular (e.g., HLA-B*46:01) that could be associated with more-severe infection, as previously shown with SARS-CoV (49). Indeed, we further compare SARS-CoV and SARS-CoV-2 peptide presentation data and note a high degree of similarity between the two across HLA types. Finally, this is the first report to present global distributions of HLA types and haplotypes with potential epidemiological ramifications in the setting of the current pandemic. We found that, in general, there is no correlation between the HLA allelic frequency in the population and allelic capacity to bind SARS-CoV or SARS-CoV-2 peptides, irrespective of the estimated timing of peptide production during the viral replication cycle. While we are not aware of any studies explicitly reporting the relationship between human coronavirus epitope abundance and immune response, there are vaccinia virus data that suggest that early peptide antigens are more likely to generate CD8+ T-cell responses whereas antibody and CD4+ T-cell responses are more likely to target later mRNA expression with higher peptide abundance in the virion (53).
We note, however, several limitations to our work. First and foremost, while we note that a few of our binding affinity predictions were borne out in experimentally validated SARS-CoV peptides (see Table S4 in the supplemental material), we acknowledge that ours was a study performed entirely in silico. As we are unable to obtain individual-level HLA typing and clinical outcome data for any real-world COVID-19 populations at this time, the data presented are theoretical in nature and are subject to many of the same limitations implicit in the MHC binding affinity prediction tool(s) upon which it is based. As such, we are unable to assess the relative importance of HLA type compared to known disease-modifying risk factors such as age and clinical comorbidities (4–9). We further note that peptide-MHC binding affinity is limited in its utility as a predictor of subsequent T-cell responses (54–56), and we did not study T-cell responses here. As such, we are ill-equipped to explore phenomena such as original antigenic sin (57–59), where prior exposure to a closely related infection(s) might trigger T-cell anergy (60–62) or immunopathogenesis (63) in the setting of a novel infection. We explored only a limited set of 145 well-studied HLA alleles but note that this analysis could be performed across a wider diversity of genotypes (48). Additionally, we did not assess genotypic heterogeneity or in vivo evolution of SARS-CoV-2, which could modify the repertoire of viral epitopes presented or could otherwise modulate virulence in an HLA-independent manner (64, 65) (https://nextstrain.org/ncov). We also did not address the potential for individual-level genetic variation in other proteins (e.g., angiotensin converting enzyme 2 [ACE2] or transmembrane serine protease 2 [TMPRSS2], essential host proteins for SARS-CoV-2 priming and cell entry [66]) to modulate the host-pathogen interface.
Unless and until the findings we present here are clinically validated, they should not be employed for any clinical purposes. However, we do at this juncture recommend integrating HLA testing into clinical trials and pairing HLA typing with COVID-19 testing where feasible to more rapidly develop and deploy a predictor(s) of viral severity in the population and, potentially, to tailor future vaccination strategies to genotypically at-risk populations. This approach may have additional implications for the management of a broad array of other viruses.