Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis.
Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis.
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DOI：
10.1371/journal.pbio.0030404
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发表时间：
2005-12
期刊：
影响因子：
9.8
通讯作者：
Hammerschmidt, Wolfgang
中科院分区：
文献类型：
--
作者：
Altmann, Markus;Hammerschmidt, Wolfgang
已知DNA病毒如疱疹病毒编码细胞抗凋亡病毒Bcl-2蛋白（vBcl-2s）的同源物，其在病毒合成期间保护病毒免于其宿主细胞中的凋亡。Epstein-Barr病毒（EBV）是一种人类肿瘤病毒，也是γ-疱疹病毒的重要成员，其感染原代静息B淋巴细胞以建立潜伏感染并在体外产生增殖的、生长转化的B细胞。在这些细胞中，11个有助于细胞转化的病毒基因持续表达。EBV还编码两个vBcl-2基因，其作用尚不清楚。在这里，我们表明，两个vBcl-2基因的遗传失活残疾EBV的能力，转化初级静息B淋巴细胞。用vBcl-2阴性病毒感染的原代B细胞没有进入细胞周期，并死于立即凋亡。细胞凋亡被废除，其中vBcl-2基因在感染后的第一个24小时内表达最大。然而，在潜伏感染期间，vBcl-2基因的表达变得不可检测。因此，两种vBcl-2同源物对于初始细胞转化都是必需的，但是一旦建立潜伏感染就变得不稳定。由于长寿，潜伏感染的记忆B细胞和EBV相关的B细胞淋巴瘤是来自EBV感染的促凋亡生发中心B细胞，我们得出结论，vBcl-2基因是必不可少的初始逃避细胞凋亡在体内病毒建立一个潜伏感染或导致细胞转化或两者兼而有之。静息B淋巴细胞由人肿瘤病毒的转化显示需要vBcl-2基因，其消除宿主细胞凋亡。一旦潜伏感染建立，这些基因就不需要了。
DNA viruses such as herpesviruses are known to encode homologs of cellular antiapoptotic viral Bcl-2 proteins (vBcl-2s), which protect the virus from apoptosis in its host cell during virus synthesis. Epstein-Barr virus (EBV), a human tumor virus and a prominent member of γ-herpesviruses, infects primary resting B lymphocytes to establish a latent infection and yield proliferating, growth-transformed B cells in vitro. In these cells, 11 viral genes that contribute to cellular transformation are consistently expressed. EBV also encodes two vBcl-2 genes whose roles are unclear. Here we show that the genetic inactivation of both vBcl-2 genes disabled EBV's ability to transform primary resting B lymphocytes. Primary B cells infected with a vBcl-2-negative virus did not enter the cell cycle and died of immediate apoptosis. Apoptosis was abrogated in infected cells in which vBcl-2 genes were maximally expressed within the first 24 h postinfection. During latent infection, however, the expression of vBcl-2 genes became undetectable. Thus, both vBcl-2 homologs are essential for initial cellular transformation but become dispensable once a latent infection is established. Because long-lived, latently infected memory B cells and EBV-associated B-cell lymphomas are derived from EBV-infected proapoptotic germinal center B cells, we conclude that vBcl-2 genes are essential for the initial evasion of apoptosis in cells in vivo in which the virus establishes a latent infection or causes cellular transformation or both. The transformation of resting B-lymphocytes by a human tumor virus is shown to require vBcl-2 genes, which abrogate host cell apoptosis. These genes are not required once latent infection is established.