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IntroductionReactivation of cytomegalovirus (CMV) and Epstein–Barr virus (EBV) is a major complication in immunocompromised patients, and understanding donor variability in antiviral immunity is essential for optimizing adoptive T-cell therapy. This study aimed to identify immunogenetic determinants of virus-specific T-cell responses in healthy donors to guide donor selection.MethodsCMV- and EBV-specific T-cell responses were characterized using flow cytometry and IFN-g ELISpot after stimulation with peptide pools, followed by integrated analyses correlating the response magnitude with human leukocyte antigen (HLA) class I and II alleles, HLA haplotypes, and HLA-G 3′UTR polymorphisms. ResultsCMV 65-kDa phosphoprotein (pp65) induced stronger CD8+ and CD4+ T-cell responses than immediate early 1 (IE1), whereas the EBV consensus peptides preferentially activated CD8+ T cells. Several HLA alleles and linked haplotypic backgrounds were associated with enhanced or reduced CMV-specific T-cell responses, including an A*01:01~C*07:01~B*08:01~DRB1*03:01~DQB1*02:01 haplotype enriched among low responders. For EBV, several HLA-restricted alleles were associated with stronger peptide-specific activation, supporting the broad immunogenicity of the consensus peptide pool. Moreover, HLA-G 3′UTR polymorphisms selectively modulated the CMV-specific IFN-g+ CD8+ T-cell frequencies. DiscussionTogether, these results indicate that classical and non-classical HLA variations are associated with inter-donor differences in antiviral T-cell response in an antigen- and virus-dependent manner, providing a translational framework to refine donor selection and improve the design of T-cell-based immunotherapies.