Influence of HLA Class I and II Polymorphisms on COVID-19 Severity in a South Brazilian Population

The high variability of human leukocyte antigen (<i>HLA</i>) genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between <i>HLA class I</i> (<i>A</i>, <i>B</i>) and <i>class II</i> (<i>DRB1</i>) polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. <i>HLA</i> typing was performed using PCR-SSO and Luminex™ technology. The <i>DRB1*11</i> allelic group was significantly associated with protection against severe and critical cases, while <i>DRB1*15</i> was associated with increased risk; both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: <i>B*49</i> and <i>B*08</i> (risk); and <i>B*37</i>, <i>B*50</i>, and <i>A*03</i> (protection). In silico analysis revealed that the <i>DRB1*15</i> allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while <i>DRB1*11:01</i> binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of <i>class II HLA</i>, particularly <i>DRB1</i>, in modulating COVID-19 severity.