Peptidome‐wide association analysis of Epstein−Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma

Abstract

AbstractHuman leukocyte antigen (HLA) molecules are essential for presenting Epstein−Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA‐bound EBV peptides and NPC risk through in silico HLA‐peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA‐target sequencing was performed. HLA‐peptide binding prediction for EBV, followed by peptidome‐wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high‐risk mutations were analyzed. We found that NPC‐associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA‐A alleles (p = 3.10 × 10−4 for immunogenic proteins and p = 8.10 × 10−5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC‐risk effect (padj = 3.77 × 10−4) and supertype A03 presented an NPC‐protective effect (padj = 4.89 × 10−4). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC‐risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC‐risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.