Epstein–Barr virus (EBV) infects more than 95% of adults worldwide but is associated with endemic nasopharyngeal carcinoma (NPC) specifically in southern China1,2,3,4. Here, through a stepwise host–EBV genome interaction analysis, we identify a genetic interaction between HLA-A*11:01 and the high-risk EBV variant 85841G as a key determinant of NPC risk. Individuals carrying a susceptible HLA-A background (HLA-A*11:01− or HLA-A*02:07+) and infected with the high-risk 85841G EBV form a dual-risk subgroup with substantially elevated, interaction-driven NPC risk, far exceeding the effects of host or virus alone. This dual-risk subgroup comprises 20.5% of the population and accounts for approximately 47% of NPC cases. We show that EBV 85841G encodes an EBNA3B peptide that binds to HLA-A*11:01 and elicits specific T cell responses capable of lysing EBV+ B cells transformed by 85841G-carrying strains, and is associated with reduced salivary viral load and lower NPC risk among A*11:01 carriers. Evolutionary analysis reveals that 85841G arose via ancient recombination events between northern and southern EBV and subsequently underwent clonal expansion in southern China, leading to co-enrichment of interacting host and viral risk factors that, in turn, contribute to NPC endemicity. These findings reveal a markedly stratified, interaction-driven risk architecture in NPC and highlight opportunities for precision prevention.
EB病毒（EBV）感染全球超过95%的成年人，但在中国南方地区特异性与地方性鼻咽癌（NPC）相关。本研究通过逐步的宿主-EBV基因组相互作用分析，发现HLA-A*11:01与高风险EBV变异体85841G之间的遗传互作是NPC风险的关键决定因素。携带易感HLA-A背景（HLA-A*11:01−或HLA-A*02:07+）且感染高风险85841G型EBV的个体构成双重风险亚组，其NPC风险显著升高，且由相互作用驱动，远超过宿主或病毒单独作用。该双重风险亚组占人群的20.5%，却贡献了约47%的NPC病例。研究表明，EBV 85841G编码一种与HLA-A*11:01结合的EBNA3B肽段，能够引发特异性T细胞应答，裂解由携带85841G的病毒株转化的EBV阳性B细胞，并且在A*11:01携带者中与较低的唾液病毒载量及更低的NPC风险相关。进化分析揭示，85841G是通过北方与南方EBV之间的古老重组事件产生，随后在中国南方发生克隆扩增，导致相互作用的宿主与病毒风险因素共同富集，从而促成NPC的地方性流行。这些发现揭示了NPC中高度分层、相互作用驱动的风险结构，并为精准预防提供了新机遇。
EBV strain interacts with host HLA to drive nasopharyngeal carcinoma risk
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