Correia Samantha, Palser Anne, Elgueta Karstegl Claudio, Middeldorp Jaap M, Ramayanti Octavia, Cohen Jeffrey I, Hildesheim Allan, Fellner Maria Dolores, Wiels Joelle, White Robert E, Kellam Paul, Farrell Paul J
Section of Virology, Imperial College Faculty of Medicine, Norfolk Place, London, United Kingdom.
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
J Virol. 2017 Jul 12;91(15). doi: 10.1128/JVI.00375-17. Print 2017 Aug 1.
Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains, named QCIGP, results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through single-nucleotide polymorphisms (SNPs) in the primary miRNA outside the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future, more directed analysis of association of specific EBV variations with EBV biology and EBV-associated diseases. Incidence of diseases associated with EBV varies greatly in different parts of the world. Thus, relationships between EBV genome sequence variation and health, disease, geography, and ethnicity of the host may be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focusing on variation in LMP1, Zp, gp350, EBNA1, and the BART miRNA cluster 2, new relationships with the known type 1/type 2 strains are demonstrated, and a novel classification of EBNA1 and the BART miRNAs is proposed.
来自大约200种爱泼斯坦-巴尔病毒（EBV）菌株的扩大集合的病毒基因序列，包括许多原始分离株，已被用于研究关键病毒基因区域的变异，特别是潜伏膜蛋白1（LMP1）、Zp、糖蛋白350（gp350）、EB病毒核抗原1（EBNA1）和BART微小RNA（miRNA）簇2。对来自广泛地理和种族背景人群的唾液样本进行1型和2型EBV的测定表明，一小部分健康的英国白种人主要携带2型EBV。Zp和gp350变体与2型EBV的连锁可能是由于它们的基因与EBNA3基因座相邻，EBNA3基因座是1型/2型区分的主要决定因素之一。对EBNA1 DNA结合域进行系统发育分析，得出一种名为QCIGP的新分类，但它与1型/2型分类无关。通过成熟miRNA序列之外的初级miRNA中的单核苷酸多态性（SNP），BART簇2 miRNA区域被分为三个主要变体。这些SNP可导致中国和印度尼西亚鼻咽癌（NPC）样本中经常出现的BART变体的一些miRNA表达水平改变。本文确定的EBV基因变体为未来更有针对性地分析特定EBV变异与EBV生物学及EBV相关疾病的关联提供了基础。与EBV相关的疾病发病率在世界不同地区差异很大。因此，EBV基因组序列变异与宿主健康、疾病、地理和种族之间的关系可能对理解EBV在疾病中的作用以及开发有效的EBV疫苗很重要。本文提供了迄今为止对与这些疾病及拟议的EBV疫苗相关的特定EBV基因变异最全面的分析。通过关注LMP1、Zp、gp350、EBNA1和BART miRNA簇2的变异，证明了与已知的1型/2型菌株的新关系，并提出了EBNA1和BART miRNA的新分类。
