Susceptibility and Severity of COVID-19 Are Both Associated With Lower Overall Viral–Peptide Binding Repertoire of HLA Class I Molecules, Especially in Younger People

Abstract

An important number of studies have been conducted on the potential association between human leukocyte antigen (<i>HLA</i>) genes and COVID-19 susceptibility and severity since the beginning of the pandemic. However, case-control and peptide-binding prediction methods tended to provide inconsistent conclusions on risk and protective <i>HLA</i> alleles, whereas some researchers suggested the importance of considering the overall capacity of an individual's HLA Class I molecules to present SARS-CoV-2-derived peptides. To close the gap between these approaches, we explored the distributions of <i>HLA-A</i>, <i>-B</i>, <i>-C</i>, and <i>-DRB1</i> 1st-field alleles in 142 Iranian patients with COVID-19 and 143 ethnically matched healthy controls, and applied <i>in silico</i> predictions of bound viral peptides for each individual's HLA molecules. Frequency comparison revealed the possible predisposing roles of <i>HLA-A*03</i>, <i>B*35</i>, and <i>DRB1*16</i> alleles and the protective effect of <i>HLA-A*32</i>, <i>B*58</i>, <i>B*55</i>, and <i>DRB1*14</i> alleles in the viral infection. None of these results remained significant after multiple testing corrections, except <i>HLA-A*03</i>, and no allele was associated with severity, either. Compared to peptide repertoires of individual HLA molecules that are more likely population-specific, the overall coverage of virus-derived peptides by one's HLA Class I molecules seemed to be a more prominent factor associated with both COVID-19 susceptibility and severity, which was independent of affinity index and threshold chosen, especially for people under 60 years old. Our results highlight the effect of the binding capacity of different HLA Class I molecules as a whole, and the more essential role of <i>HLA-A</i> compared to <i>HLA-B</i> and <i>-C</i> genes in immune responses against SARS-CoV-2 infection.