Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.
Chang-Mi DengTong-Min WangYong-Qiao HeWen-Li ZhangWen-Qiong XueDan-Hua LiDa-Wei YangQiao-Ling WangYing LiaoHua DiaoCheng-Tao JiangJiang-Bo ZhangLei-Lei YuanXue-Yin ChenTing ZhouXi-Zhao LiPei-Fen ZhangXiao-Hui ZhengShao-Dan ZhangYe-Zhu HuMiao XuMu-Sheng ZengLin FengWei-Hua JiaPublished in: Journal of medical virology (2023)
Human 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 (p adj = 3.77 × 10 -4 ) and supertype A03 presented an NPC-protective effect (p adj = 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.