Epstein-Barr virus and B-cell co-opted functions of the endogenous retrovirus envelope protein, Syncytin-1

项目摘要 人类内源性逆转录病毒（HERVs）的异常表达与病理学增强有关 在一些癌症和自身免疫性疾病（1，2）。其中一个HERV元件是蛋白质合胞素- 1，由ERVW 1基因编码，是胎盘发育所必需的。虽然这些元素是 胚胎发育后表观遗传学沉默，外源性病毒感染，如EB病毒 (EBV)，与HERV的表达增强有关（3-7）。EBV是一种γ-疱疹病毒， 传染性单核细胞增多症并与许多癌症相关，包括伯基特淋巴瘤（BL）， 鼻咽癌、何杰金氏病和其他淋巴组织增生性疾病。没有疫苗， 抗病毒药物可用，EB病毒是一种重要的病原体进行研究。EBV的原发性感染始于其 附着、融合和进入口咽上皮细胞。EB病毒然后扩散到记忆B细胞， 在宿主的一生中持续存在，通常处于潜伏状态。在潜伏期，只有一小部分EBV基因被激活。 表示（8）。周期性地，EBV在B细胞亚群中经历裂解活化以在群体中持续存在。 重要的是，EBV的裂解活化不仅增加了发展EBV相关癌症的风险， 在免疫功能低下的宿主中，但也可用于以已知的方法治疗EBV相关的癌症。 作为溶瘤治疗。裂解激活的特征在于超过80%的EBV基因表达，许多EBV基因表达是由细胞内的细胞因子引起的。 其用于免疫逃避、细胞凋亡的调节和宿主蛋白质合成的阻断。后一 这一现象导致大多数宿主基因的下调，称为全局宿主关闭，并且优先的宿主基因被关闭。 病毒基因的表达（9）。尽管全球主机关闭，我发现HERV元件ERVW 1，编码 合胞素-1在感染的B细胞中EBV的裂解活化期间转录物和蛋白质水平均增加。这个， 再加上类似的表观遗传机制使HERVs和潜伏性EBV沉默的事实，使我预测 EBV在裂解性复制过程中可能出于特定目的而保留和/或激活合胞素-1。 本研究旨在阐明Syncytin-1在EBV感染B细胞过程中的作用。它将揭示为什么合胞素-1 研究 将进一步表征合胞素-1耗竭和诱变对B细胞生物学的影响，以及 Syncytin-1广泛地与B细胞蛋白质相互作用，特别是与PI 3 K/Akt/mTOR信号转导的相互作用 已知其触发EBV裂解性复制、B细胞存活和增殖。拟议的研究旨在 揭示了合胞素-1在淋巴增生性疾病和B细胞淋巴瘤中的作用机制。 尽管宿主细胞关闭，但通过描绘合胞素-1在EBV裂解周期中的影响而上调。 假设：我假设合胞素-1被EBV选择性地保留，因为它在增强溶解性细胞因子中起作用。 复制的我还假设合胞素-1通过促进细胞增殖在B细胞生物学中发挥作用。 目的1：明确Syncytin-1在EB病毒裂解周期中的作用。 目的2：探讨Syncytin-1在B细胞增殖中的作用。

Project Summary Aberrant expression of human endogenous retroviruses (HERVs) has been associated with enhanced pathology in a number of cancers and autoimmune diseases (1, 2). One of these HERV elements is the protein Syncytin- 1, encoded by the ERVW1 gene, and is essential for placental development. Although these elements are epigenetically silenced after embryonic development, exogenous viral infections, such as Epstein-Barr virus (EBV), have been linked to enhanced expression of HERVs (3-7). EBV, a gamma-herpesvirus, is the cause of infectious mononucleosis and associated with a number of cancers including Burkitt lymphoma (BL), nasopharyngeal cell carcinoma, Hodgkin’s disease, and other lymphoproliferative diseases. With no vaccine or antiviral drug available, EBV is an important pathogen to study. Primary infection with EBV begins with its attachment, fusion, and entry into oropharyngeal epithelial cells. EBV then spreads to memory B cells where it persists for the life of the host, generally in a latent state. During latency, only a small subset of EBV genes are expressed (8). Periodically, EBV undergoes lytic activation in a subset of B cells to persist in the population. Importantly, lytic activation of EBV not only increases risks for development of EBV-related cancers, particularly in immunocompromised hosts, but may also be exploited to treat EBV-associated cancers in an approach known as oncolytic therapy. Lytic activation is characterized by the expression of over 80% of EBV genes, many of which serve in immune evasion, regulation of apoptosis, and blockade of host protein synthesis. This latter phenomenon results in the downregulation of most host genes, known as global host shutoff, and the preferential expression of viral genes (9). Despite global host shutoff, I find that the HERV element ERVW1, which encodes Syncytin-1, increases in both transcript and protein levels during lytic activation of EBV in infected B cells. This, coupled with the fact that similar epigenetic mechanisms silence both HERVs and latent EBV, leads me to predict that EBV may spare and/or activate Syncytin-1 for a specific purpose during lytic replication. This study will elucidate the functions of Syncytin-1 during EBV infection of B cells. It will reveal why Syncytin-1 The study will further characterize the consequences of Syncytin-1 depletion and mutagenesis on B cell biology as well as the interactions of Syncytin-1 broadly with B cell proteins and specifically with the PI3K/Akt/mTOR signaling pathway, known to trigger EBV lytic replication, B cell survival, and proliferation. The proposed studies are aimed at revealing mechanisms governing the role of Syncytin-1 in lymphoproliferative diseases and B cell lymphomas. is upregulated despite host cell shutoff by delineating Syncytin-1’s influence during the EBV lytic cycle. Hypothesis: I hypothesize that Syncytin-1 is selectively spared by EBV because it has a role in potentiating lytic replication. I also hypothesize that Syncytin-1 plays a role in B cell biology by promoting cell proliferation. Aim 1: Define the contribution of Syncytin-1 to Epstein-Barr virus lytic cycle. Aim 2: Determine the functional role of Syncytin-1 in B cell proliferation.