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(HERV)的异常表达与病理增强有关 在一些癌症和自身免疫性疾病中(1，2)。其中一个HERV元件是蛋白质合胞素- 1，由ERVW1基因编码，对胎盘发育是必需的。尽管这些元素是 胚胎发育后表观遗传沉默，外源性病毒感染，如爱泼斯坦-巴尔病毒 (EBV)与HERV表达增强有关(3-7)。EB病毒是一种伽玛疱疹病毒，是导致 传染性单核细胞增多症，并与包括Burkitt淋巴瘤(BL)在内的许多癌症有关， 鼻咽癌、霍奇金氏病和其他淋巴增生性疾病。没有疫苗或 在现有的抗病毒药物中，EBV是值得研究的重要病原体。EBV的原发感染始于其 附着、融合和进入口咽上皮细胞。然后EBV传播到记忆B细胞，在那里它 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基因是 表示(8)。周期性地，EBV在B细胞亚群中经历裂解激活，以持续存在于人群中。 重要的是，EBV的裂解激活不仅增加了EBV相关癌症的发生风险，尤其是 在免疫受损的宿主中，但也可能被利用来治疗EBV相关癌症，以一种已知的方法 作为溶瘤治疗。裂解激活的特征是超过80%的EBV基因的表达，许多 它们起免疫逃避、调节细胞凋亡和阻断宿主蛋白质合成的作用。后者 这一现象导致大多数寄主基因下调，称为全局寄主关闭，并优先 病毒基因的表达(9)。尽管全局主机关闭，但我发现Herv元素ERVW1，它编码 在受感染的B细胞中，在EBV裂解激活过程中，Syncytin-1的转录和蛋白水平都会增加。这, 再加上类似的表观遗传机制使HERV和潜伏的EBV沉默，这让我预测 该EBV可在裂解复制期间出于特定目的而备用和/或激活Syncytin-1。 本研究旨在阐明Syncytin-1在EB病毒感染B细胞过程中的作用。它将揭示为什么Syncytin-1 这项研究 将进一步表征Syncytin-1耗尽和突变对B细胞生物学以及 Syncytin-1广泛与B细胞蛋白的相互作用，特别是与PI3K/Akt/mTor信号通路的相互作用 途径，已知触发EBV裂解复制、B细胞存活和增殖。拟议的研究旨在 揭示Syncytin-1在淋巴增生性疾病和B细胞淋巴瘤中的作用机制。 通过描绘合胞素-1‘S在EB病毒裂解周期中的影响，在宿主细胞关闭的情况下上调。 假设：我假设EBV选择性地不使用Syncytin-1，因为它具有增强溶血的作用 复制。我还假设Syncytin-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：探讨合胞素-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.