Epistatic evolution drives HLA-dependent CD8+ T Cell escape risk in diverse populations
Hamelin, D. J.; Grenier, J.-C.; Poujol, R.; Bourdin, B.; Pare, B.; Simpson, S.; Smith, M.; Decaluwe, H.; Caron, E.; Hussin, J.
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Understanding how viral evolution shapes HLA-dependent T cell escape is crucial to identify individuals at risk of reduced cellular immunity to emerging variants. Nevertheless, we lack frameworks to model HLA diversity and the evolutionary feasibility of T cell-evading mutations. Here, we construct an HLA map capturing variation in epitope specificity across HLA-typed cohorts. Enhancing this framework with SARS-CoV-2 CD8 T cell escape reveals heterogeneous escape across HLA-defined groups, with clusters enriched for HLA-B*07:02, HLA-A*03:01 and HLA-A*02:01 showing higher epitope loss. To assess the evolutionary plausibility of escape, we model viral sequence fitness using an epistasis-aware protein language approach trained on coronaviruses to systematically score mutations across viral lineages. We find that the fitness effect of mutations dynamically changes with evolving sequence context, and that T cell-evading mutations become fitter with additional escape mutations. This study links host HLA diversity to viral fitness landscapes for surveillance and vaccine design.
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