Neutralizing Antibodies in Acute and Persistent Epstein-Barr Virus Infection

急性和持续性 Epstein-Barr 病毒感染中的中和抗体

• 批准号: 8965501
• 负责人: Frederick C. Wang
• 金额: $ 61.27万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965501
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adult; Animal Model; B-Lymphocytes; Binding; Binding Sites; Biology; Burkitt Lymphoma; Clinical Data; Complement 3d Receptors; Complex; Cross Infection; Data; Development; EBV-associated disease; Epithelial; Epithelial Cells; Epstein-Barr Virus Infections; Event; Foundations; Genes; Germ Cells; Glycoproteins; Goals; Hairy Leukoplakia; Health; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune Targeting; Immune response; Infection; Infectious Mononucleosis; Integrin Binding; Integrins; Intervention; Life; Lymphocryptovirus; Macaca mulatta; Malignant Neoplasms; Mediating; Membrane Glycoproteins; Modeling; Nasopharynx Carcinoma; Oral; Oral mucous membrane structure; Outcome; Pathway interactions; Patients; Penetration; Phase; Production; Reagent; Role; Staging; Stomach; Stomach Carcinoma; Testing; Therapeutic; Transplant Recipients; Tropism; Uncertainty; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Virus Receptors; arm; base; cell type; effective therapy; immunosuppressed; in vivo; infected B cell; innovation; insight; lytic replication; neutralizing antibody; neutralizing monoclonal antibodies; novel; oral infection; persistent EBV infection; pre-clinical; prevent; research study; secondary infection; therapeutic vaccine; transmission process; vaccine development

 DESCRIPTION (provided by applicant): Our goal is to better understand how Epstein-Barr virus infects humans in order to develop more effective therapeutics that prevent or treat EBV-induced diseases. Specifically, this project focuses on how neutralizing antibodies that block either EBV infection of B or epithelial cells impact acute and persistent infection of the host aftr oral transmission. EBV infects B cells and epithelial cells through different viral proteins and receptors, but which cell types are critical for the initial phases of oral infection and viral amplification are unknown. More importantly, neutralizing B cell infection is being pursued as the basis for an EBV vaccine with little pre-clinical or clinical data to support the concept that neutralizing antibodies against EBV infection of B cells will have any impact on oral virus challenge. We use neutralizing antibodies as a probe in the most accurate animal model for EBV infection to ask whether this arm of the immune response alone is sufficient to disrupt acute and persistent infection upon oral virus challenge. 72A1 is the most studied of only a few known EBV neutralizing monoclonal antibodies (mab), and it binds the EBV major membrane glycoprotein, gp350, to inhibit EBV attachment to B cells. In order to use 72A1 in the rhesus macaque animal model for EBV infection, we replaced the native gp350 gene in the rhesus lymphocryptovirus (rhLCV) with EBV gp350. This chimeric virus can be neutralized by 72A1 and infects rhesus macaques, providing a novel animal model for studying EBV gp350-specific reagents directly in vivo. Epithelial cell infection is mediated by binding of the EBV glycoprotein H and L complex to integrins. gH and gL are much more well conserved in rhLCV and a potent neutralizing mab, E1D1, that prevents epithelial cell infection cross-reacts with the integrin binding site on rhLCV gH/gL. These neutralizing mabs will be used to experimentally test the role of B and epithelial cell infection in acute and persistent infection after oral challenge withthe chimeric virus in rhesus macaques. An important strength of this proposal is its advancement of our basic understanding of EBV biology, as well as its immediate translational impact. Better understandings of the early events in EBV infection after oral transmission and experimental testing for the role of neutralizing antibodies targeting either B or epithelial cell infection proide a foundation for EBV vaccine development based on mechanism, rather than trial and error. In addition, these studies can provide important pre-clinical data to advance the use of neutralizing mabs as a therapeutic to prevent EBV-induced disease in immunosuppressed, EBV-naive hosts.

 描述（由申请人提供）：我们的目标是更好地了解 Epstein-Barr 病毒如何感染人类，以便开发更有效的疗法来预防或治疗 EBV 引起的疾病。具体而言，该项目重点研究如何中和抗体来阻止 EBV 感染。 B 细胞或上皮细胞在口腔传播后影响宿主的急性和持续感染 EB 病毒通过不同的病毒蛋白和受体感染 B 细胞和上皮细胞，但哪些细胞类型对于初始阶段至关重要。更重要的是，人们正在寻求中和 B 细胞感染作为 EBV 疫苗的基础，但几乎没有临床前或临床数据支持针对 B 细胞 EBV 感染的中和抗体将具有任何作用的概念。我们在最准确的 EBV 感染动物模型中使用中和抗体作为探针，以探究仅靠这一免疫反应臂是否足以破坏 72A1 口腔病毒攻击后的急性和持续性感染。仅少数已知的 EBV 中和单克隆抗体 (mab)，它与 ​​EBV 主要膜糖蛋白 gp350 结合，抑制 EBV 附着于 B 细胞。为了在恒河猴动物模型中使用 72A1 进行 EBV 感染，我们替换了 EBV 中的天然 gp350 基因。带有 EBV gp350 的恒河猴淋巴隐病毒 (rhLCV) 这种嵌合病毒可以被 72A1 和 中和。感染恒河猴，为直接在体内研究 EBV gp350 特异性试剂提供了一种新的动物模型。上皮细胞感染是通过 EBV 糖蛋白的结合介导的。 整合素的 H 和 L 复合物在 rhLCV 中更加保守，并且有效的中和单克隆抗体 E1D1 可防止上皮细胞感染与 rhLCV gH/gL 上的整合素结合位点发生交叉反应。实验测试 B 细胞和上皮细胞感染在恒河猴口服嵌合病毒后的急性和持续感染中的作用。该提案的优势在于它增进了我们对 EBV 生物学的基本了解，以及更好地了解口服传播后 EBV 感染的早期事件以及针对 B 细胞或上皮细胞的中和抗体的作用的实验测试。感染为基于机制而不是试验和错误的 EBV 疫苗开发奠定了基础。此外，这些研究可以提供重要的临床前数据，以推进中和单克隆抗体作为治疗剂的使用，以预防免疫抑制的 EBV 诱发的疾病。未接触 EBV 的宿主。