Department of Molecular Genetics and Microbiology, Center for Virology, Duke University Medical Center, Durham, North Carolina, USA.
J Virol. 2012 Oct;86(20):11096-106. doi: 10.1128/JVI.01069-12. Epub 2012 Aug 1.
Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression to immortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changes following primary B-cell infection, both during initial proliferation and through transformation into lymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transition from resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAs changed uniquely from early proliferation through LCL outgrowth. We identified constitutively and dynamically EBV-regulated biological processes, protein classes, and targets of specific transcription factors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathway were highly enriched. However, the transition from early to long-term outgrowth was characterized by genes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-κB activity. It was previously thought that the major viral protein responsible for NF-κB activation, latent membrane protein 1 (LMP1), is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1 expression and NF-κB activity are not evident until 3 weeks after primary B-cell infection. Furthermore, heterologous NF-κB activation during the first week after infection increased the transformation efficiency, while early NF-κB inhibition had no effect on transformation. Rather, inhibition of NF-κB was not toxic to EBV-infected cells until LMP1 levels and NF-κB activity were high. These data collectively highlight the dynamic nature of EBV-regulated host gene expression and support the notion that early EBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from that of LCLs.
EB 病毒（EBV）是一种致癌性人类疱疹病毒，可显著重排宿主基因表达，使原代 B 细胞永生化。在这项研究中，我们分析了 EBV 感染原代 B 细胞后宿主基因表达的变化，包括初始增殖和转化为淋巴母细胞系（LCL）期间。虽然大多数 EBV 调节的 mRNA 在从静止、未感染的 B 细胞过渡到初始 B 细胞增殖的过程中发生了变化，但大量的 mRNA 在从早期增殖到 LCL 生长的过程中发生了独特的变化。我们确定了 EBV 调节的固有和动态生物学过程、蛋白质类别以及特定转录因子的靶标。感染后早期，与增殖、应激反应和 p53 通路相关的基因高度富集。然而，从早期到长期生长的过渡特征是涉及凋亡抑制、肌动蛋白细胞骨架和 NF-κB 活性的基因。以前认为，负责 NF-κB 激活的主要病毒蛋白，潜伏膜蛋白 1（LMP1），在感染后 2 天内表达。我们的数据表明，虽然这是正确的，但 LCL 水平的 LMP1 表达和 NF-κB 活性直到原代 B 细胞感染后 3 周才明显。此外，感染后第一周的异源 NF-κB 激活增加了转化效率，而早期 NF-κB 抑制对转化没有影响。相反，直到 LMP1 水平和 NF-κB 活性升高，NF-κB 抑制对 EBV 感染细胞才没有毒性。这些数据共同强调了 EBV 调节的宿主基因表达的动态性质，并支持这样一种观点，即早期 EBV 感染的增殖 B 细胞具有与 LCL 根本不同的生长和存活表型。
