INHIBITION OF ANTIGEN-PROCESSING BY THE INTERNAL REPEAT REGION OF THE EPSTEIN-BARR-VIRUS NUCLEAR ANTIGEN-1
INHIBITION OF ANTIGEN-PROCESSING BY THE INTERNAL REPEAT REGION OF THE EPSTEIN-BARR-VIRUS NUCLEAR ANTIGEN-1
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DOI：
10.1038/375685a0
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发表时间：
1995-06-22
期刊：
影响因子：
64.8
通讯作者：
MASUCCI, MG
中科院分区：
文献类型：
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作者：
LEVITSKAYA, J;CORAM, M;MASUCCI, MG
EB病毒（EBV）编码的核抗原（EBNA 1）在潜伏性EBV感染的B淋巴细胞中表达，这些淋巴细胞在健康病毒携带者中持续存在（1，2），并且是在所有与EBV相关的恶性肿瘤中定期检测到的唯一病毒蛋白（3，4）。尚未证实主要组织相容性复合体（MHC）I类限制性、EBNA 1特异性细胞毒性T淋巴细胞（CTL）应答（3，5）。使用编码嵌合蛋白的重组牛痘病毒，所述嵌合蛋白含有免疫显性人白细胞抗原A11限制性CTL表位，EBNA 4蛋白的氨基酸416-424（6），插入完整EBNA 1内，或插入缺乏内部Gly-Ala重复序列的EBNA 1缺失突变体内，我们证明Gly-Ala重复序列产生顺式作用抑制信号，干扰抗原加工和MHC I类限制性呈递。在416-424表位下游插入Gly-Ala重复序列抑制了嵌合EBNA 4蛋白的CTL识别。结果突出了一个以前未知的机制，从CTL监视病毒逃逸，并支持这样的观点，即表达EBNA 1的细胞对CTL介导的排斥反应的抗性是EBV持久性和发病机制的关键要求。
THE Epstein-Barr virus (EBV)-encoded nuclear antigen (EBNA1) is expressed in latently EBV-infected B lymphocytes that persist for life in healthy virus carriers(1,2) and is the only viral protein regularly detected in all malignancies associated with EBV(3,4). Major histocompatibility complex (MHC) class I-restricted, EBNA1-specific cytotoxic T lymphocyte (CTL) responses have not been demonstrated(3,5). Using recombinant vaccinia viruses encoding chimaeric proteins containing an immunodominant human leukocyte antigen A11-restricted CTL epitope, amino acids 416-424 of the EBNA4 protein(6), inserted within the intact EBNA1, or within an EBNA1 deletion mutant devoid of the internal Gly-Ala repetitive sequence, we demonstrate that the Gly-Ala repeats generate a cis-acting inhibitory signal that interferes with antigen processing and MHC class I-restricted presentation. Insertion of the Gly-Ala repeats downstream of the 416-424 epitope inhibited CTL recognition of a chimaeric EBNA4 protein. The results highlight a previously unknown mechanism of viral escape from CTL surveillance, and support the view that the resistance of cells expressing EBNA1 to rejection mediated by CTL is a critical requirement for EBV persistence and pathogenesis.