An Epstein-Barr Virus Encoded Inhibitor of Colony Stimulating Factor-1 Signaling Is an Important Determinant for Acute and Persistent EBV Infection
An Epstein-Barr Virus Encoded Inhibitor of Colony Stimulating Factor-1 Signaling Is an Important Determinant for Acute and Persistent EBV Infection
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DOI：
10.1371/journal.ppat.1003095
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发表时间：
2012-12-01
期刊：
影响因子：
6.7
通讯作者：
Wang, Fred
中科院分区：
文献类型：
--
作者：
Ohashi, Makoto;Fogg, Mark H.;Wang, Fred
急性EB病毒（EBV）感染是传染性单核细胞增多症最常见的原因。几乎所有成年人都具有终身的、持续的EBV感染，其可导致癌症的发展，包括霍奇金淋巴瘤、伯基特淋巴瘤、鼻咽癌、胃癌和免疫抑制患者中的淋巴瘤。BARF 1是一种EBV复制相关的分泌蛋白，可阻断集落刺激因子1（CSF-1）信号传导，这是一种不被任何其他病毒物种靶向的先天免疫途径。为了评估BARF 1在急性和持续性感染中的作用，我们突变了EBV相关疱疹病毒或淋巴隐病毒（LCV）中的BARF 1同源物，天然感染恒河猴，以产生不能阻断CSF-1的重组rhLCV（Delta rhBARF 1）。用Delta rhBARF 1经口攻击的恒河猴具有降低的病毒载量，表明CSF-1对于急性病毒感染是重要的。令人惊讶的是，Delta rhBARF 1在持续感染期间也与显著降低的病毒设定点相关。在经口接种Delta rhBARF 1或在rhBARF 1修复的地方用重组rhLCV感染免疫活性动物之前，通过猿猴/人类免疫缺陷病毒诱导的免疫抑制，可以恢复rhLCV持续感染期间的正常急性病毒载量和正常病毒设定点。这些结果表明，BARF 1阻断CSF-1信号传导是有效急性EBV感染的重要免疫逃避策略，也是持续EBV感染期间病毒设定点的重要决定因素。
Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis. Nearly all adult humans harbor life-long, persistent EBV infection which can lead to development of cancers including Hodgkin Lymphoma, Burkitt Lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and lymphomas in immunosuppressed patients. BARF1 is an EBV replication-associated, secreted protein that blocks Colony Stimulating Factor 1 (CSF-1) signaling, an innate immunity pathway not targeted by any other virus species. To evaluate effects of BARF1 in acute and persistent infection, we mutated the BARF1 homologue in the EBV-related herpesvirus, or lymphocryptovirus (LCV), naturally infecting rhesus macaques to create a recombinant rhLCV incapable of blocking CSF-1 (Delta rhBARF1). Rhesus macaques orally challenged with Delta rhBARF1 had decreased viral load indicating that CSF-1 is important for acute virus infection. Surprisingly, Delta rhBARF1 was also associated with dramatically lower virus setpoints during persistent infection. Normal acute viral load and normal viral setpoints during persistent rhLCV infection could be restored by Simian/Human Immunodeficiency Virus-induced immunosuppression prior to oral inoculation with Delta rhBARF1 or infection of immunocompetent animals with a recombinant rhLCV where the rhBARF1 was repaired. These results indicate that BARF1 blockade of CSF-1 signaling is an important immune evasion strategy for efficient acute EBV infection and a significant determinant for virus setpoint during persistent EBV infection.