Identification of risk and protective human leukocyte antigens in COVID-19 using genotyping and structural modeling

COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. Since innate and adaptive immune responses are elicited in COVID-19 patients, we genotyped 94 Florida patients with confirmed COVID-19 and 89 healthy controls. We identified an HLA gene, HLA-DPA1, in which specific alleles were associated with the risk of SARS-CoV-2 positivity and COVID-19 disease. HLA-DPA1*01:03 was associated with reduced incidence of SARS-CoV-2 positivity, whereas HLA-DPA1*03:01 was associated with increased risk of SARS-CoV-2 positivity. These data suggest a model in which COVID-19 severity is influenced by immunodominant peptides derived from SARS-CoV-2 preferentially presented by specific HLA-DP molecules to either protective (for asymptomatic COVID-19) or pathogenic T cells (in severe COVID-19). Although this study is limited to comparing SARS-CoV-2 positive and negative subjects, these data suggest that HLA typing of COVID-19 patients stratified for disease severity may be informative for identifying biomarkers and disease mechanisms in high-risk individuals.