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 (HLA) 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 HLA 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 HLA-A, -B, -C, and -DRB1 1st-field alleles in 142 Iranian patients with COVID-19 and 143 ethnically matched healthy controls, and applied in silico predictions of bound viral peptides for each individual’s HLA molecules. Frequency comparison revealed the possible predisposing roles of HLA-A*03, B*35, and DRB1*16 alleles and the protective effect of HLA-A*32, B*58, B*55, and DRB1*14 alleles in the viral infection. None of these results remained significant after multiple testing corrections, except HLA-A*03, 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 HLA-A compared to HLA-B and -C genes in immune responses against SARS-CoV-2 infection.

HLA variants and TCR diversity against SARS‐CoV‐2 in the pre‐COVID‐19 era

“…The observed inter-individual variability, at least for strong binders, is intriguing in the light of recent studies suggesting that functional differences in antigen presentation could be related to COVID-19 outcome (e.g., susceptibility, severity, and mortality). 10,39,40 Variability in peptide binding has also been described in different populations. 37 Both qualitative and quantitative aspects of binding could affect viral infection as discussed in Ozer and Lenz.…”

HLA variants and TCR diversity against SARS-CoV-2 in the pre-COVID-19 era

“…2D, bottom). The observed interindividual variability, at least for strong binders, is intriguing in the light of recent studies suggesting that functional differences beyond HLA polymorphism could be related to COVID-19 outcome (e.g., susceptibility, severity and mortality) 7,14 . Variability in peptide binding has also been described in different populations 12 .…”

“…As T cells are intrinsically cross-reactive, we investigated whether the anti-SARS-CoV-2 clonotypes retrieved in the cohort were sharing an homologous CDR3β sequence to sequences of clones known to be reactive to other viruses and to which donors and recipients could have potentially been exposed or had a clinically documented infection. For this purpose, we downloaded the sequences of antiviral clones specific to CMV (n=18,205 unique sequences in addition to the ones already available from 18 ), EBV (4,227), Influenza A (4,486), HPV (14), HSV2 (31), HTLV1 (167) and HCoV-HKU1 (48) from the VDJ repository 19 .…”

Long COVID in the context of social determinants of health

“…Multiple attempts have been made to identify vulnerable populations by examining the predictors of risk of infection and the severity of COVID-19. The following factors were identified as potential contributors to the disparity in exposure to the infection, morbidity, and mortality of COVID-19: race/ethnic differences, older age, living with multiple chronic conditions, genetic differences in Human Leukocyte Antigen (HLA) alleles, low socioeconomic status, and limited access to care (28)(29)(30)(31).…”