Weiss Eric R, Lamers Susanna L, Henderson Jennifer L, Melnikov Alexandre, Somasundaran Mohan, Garber Manuel, Selin Liisa, Nusbaum Chad, Luzuriaga Katherine
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Bioinfoexperts LLC, Thibodaux, Louisiana, USA.
J Virol. 2018 Jan 2;92(2). doi: 10.1128/JVI.01466-17. Print 2018 Jan 15.
Over 90% of the world's population is persistently infected with Epstein-Barr virus. While EBV does not cause disease in most individuals, it is the common cause of acute infectious mononucleosis (AIM) and has been associated with several cancers and autoimmune diseases, highlighting a need for a preventive vaccine. At present, very few primary, circulating EBV genomes have been sequenced directly from infected individuals. While low levels of diversity and low viral evolution rates have been predicted for double-stranded DNA (dsDNA) viruses, recent studies have demonstrated appreciable diversity in common dsDNA pathogens (e.g., cytomegalovirus). Here, we report 40 full-length EBV genome sequences obtained from matched oral wash and B cell fractions from a cohort of 10 AIM patients. Both intra- and interpatient diversity were observed across the length of the entire viral genome. Diversity was most pronounced in viral genes required for establishing latent infection and persistence, with appreciable levels of diversity also detected in structural genes, including envelope glycoproteins. Interestingly, intrapatient diversity declined significantly over time ( < 0.01), and this was particularly evident on comparison of viral genomes sequenced from B cell fractions in early primary infection and convalescence ( < 0.001). B cell-associated viral genomes were observed to converge, becoming nearly identical to the B95.8 reference genome over time (Spearman rank-order correlation test; = -0.5589, = 0.0264). The reduction in diversity was most marked in the EBV latency genes. In summary, our data suggest independent convergence of diverse viral genome sequences toward a reference-like strain within a relatively short period following primary EBV infection. Identification of viral proteins with low variability and high immunogenicity is important for the development of a protective vaccine. Knowledge of genome diversity within circulating viral populations is a key step in this process, as is the expansion of intrahost genomic variation during infection. We report full-length EBV genomes sequenced from the blood and oral wash of 10 individuals early in primary infection and during convalescence. Our data demonstrate considerable diversity within the pool of circulating EBV strains, as well as within individual patients. Overall viral diversity decreased from early to persistent infection, particularly in latently infected B cells, which serve as the viral reservoir. Reduction in B cell-associated viral genome diversity coincided with a convergence toward a reference-like EBV genotype. Greater convergence positively correlated with time after infection, suggesting that the reference-like genome is the result of selection.
全球超过90%的人口持续感染爱泼斯坦-巴尔病毒（EBV）。虽然EBV在大多数个体中不会引发疾病，但它是急性传染性单核细胞增多症（AIM）的常见病因，并且与多种癌症和自身免疫性疾病有关，这凸显了对预防性疫苗的需求。目前，直接从感染个体中测序的原发性、循环EBV基因组非常少。虽然预测双链DNA（dsDNA）病毒的多样性水平较低且病毒进化速率较慢，但最近的研究表明常见的dsDNA病原体（如巨细胞病毒）存在明显的多样性。在此，我们报告了从10名AIM患者队列的匹配口腔冲洗液和B细胞组分中获得的40个全长EBV基因组序列。在整个病毒基因组长度上均观察到了患者内和患者间的多样性。多样性在建立潜伏感染和持续性所必需的病毒基因中最为明显，在包括包膜糖蛋白在内的结构基因中也检测到了相当程度的多样性。有趣的是，患者内多样性随时间显著下降（<0.01），在比较原发性早期感染和恢复期B细胞组分中测序的病毒基因组时尤其明显（<0.001）。观察到与B细胞相关的病毒基因组逐渐趋同，随着时间的推移变得与B95.8参考基因组几乎相同（斯皮尔曼等级相关检验；=-0.5589，=0.0264）。多样性的降低在EBV潜伏基因中最为显著。总之，我们的数据表明，在原发性EBV感染后的相对短时间内，不同的病毒基因组序列独立地向类似参考菌株趋同。鉴定变异性低且免疫原性高的病毒蛋白对于开发保护性疫苗很重要。了解循环病毒群体中的基因组多样性是这一过程的关键步骤，感染期间宿主内基因组变异的扩展也是如此。我们报告了在原发性感染早期和恢复期从10名个体的血液和口腔冲洗液中测序的全长EBV基因组。我们的数据表明，循环EBV毒株库以及个体患者体内均存在相当大的多样性。从早期感染到持续性感染，总体病毒多样性下降，特别是在作为病毒储存库的潜伏感染B细胞中。与B细胞相关的病毒基因组多样性的降低与向类似参考的EBV基因型趋同相吻合。更大程度的趋同与感染后的时间呈正相关，这表明类似参考的基因组是选择的结果。
