Hla Impacts on the SARS-CoV-2 and MERS Spike Proteins in the Arabian Population

(1) Background: Human Leukocyte Antigen (HLA) genetics substantially impact viral infection outcomes. SARS-CoV-2 continues to evolve, potentially escaping HLA presentation and hindering immune control. Studies of HLA alleles in diverse non-Western populations are limited. We aimed to investigate whether mutations in successive SARS-CoV-2 waves have led to viral escape from common HLA class I alleles in the Saudi Arabian population. (2) Methods: Binding affinities of spike protein epitopes to common Saudi HLA alleles (HLA-A02:01, HLA-C06:02, and HLA-B51:01) were predicted across major SARS-CoV-2 strains using NetMHCpan. One-way ANOVA, one-sample t-tests, and pairwise chi-square analyses were performed to assess differences in binding affinities and epitope binding categories among strains. (3) Results: One-way ANOVA revealed significant differences in binding affinities among SARS-CoV-2 strains for HLA-A02:01 and HLA-C06:02, but not for HLA-B51:01. One-sample t-tests showed significant differences in mean binding affinity scores compared to a theoretical mean of 0 for all strain and HLA allele combinations, except for HLA-B51:01. Pairwise chi-square analyses identified significant differences in epitope binding category distribution between Alpha and Epsilon strains and between Epsilon and Gamma strains for HLA-B51:01; (4) Conclusions: SARS-CoV-2 evolution enables escape from common HLA alleles in Saudis. Tracking population-specific HLA binding profiles is key for elucidating evasion mechanisms and guiding future vaccine design against COVID-19.