HLA escape and exposure – a balancing act

Introduction:
Viruses have evolved multiple mechanisms to evade host immune responses, introducing mutations that disrupt antibody binding, T-cell recognition and HLA binding. The SARS-CoV-2 pandemic has provided a wealth of viral genomic and immunologic data allowing us to comprehensively study viral escape. Multiple studies reported spike mutations that evade neutralizing antibody responses. Here we studied the role of viral mutations on escape from HLA binding. We found that while some viral mutations lead to HLA escape, others lead to HLA exposure – i.e. the mutations exposes a novel epitope bound to HLA alleles.

Materials and Methods:
We developed a method to predict T-cell escape, via mutations that disrupt HLA presentation. The method utilizes an ensemble of state-of-the-art HLA binding prediction algorithms to assess the impact of individual mutations on the binding affinity of peptides to 27 most common HLA alleles. Over 18 million SARS-CoV-2 sequences from the GISAID database were analyzed to extract frequent mutations and their trends across time. An HLA escape score was developed to quantify the ability of a given mutation to reduce HLA binding and potentially mediate escape from T-cell recognition.

Results and Discussion:
Escape mutations were more prevalent in experimentally verified HLA binding peptides (p < 0.1×10³) and T-cell epitopes (p < 0.1×10³). HLA escape was more pronounced at HLA anchor positions within the peptide. We also identified mutations that create new HLA binding epitopes and found that overall, viral mutations lead to similar numbers of HLA exposures and HLA escapes. We further found an enrichment of HLA exposures in mutations associated with escape from antibodies.

Analysis of mutations across time revealed an increase in T-cell escape mutations, particularly during the emergence of the Delta and Omicron variants. Additional Omicron variants had significantly higher HLA exposure rates, that overall balanced the number of exposures and escapes. This observation suggests that T-cell mediated immune pressure contributes to viral evolution, especially as population immunity increases through natural infection and vaccination.

Conclusions:
Our analysis suggests that viral mutations can drive both escape and exposure from HLA presentation, highlighting the difficulty to escape T-cell recognition on a population level.