ANTI-VIRAL IL-6 APPROACH TO MITIGATE KSHV-RELATED DISEASE

减轻 KSHV 相关疾病的抗病毒 IL-6 方法

• 批准号: 8173201
• 负责人: SCOTT W WONG
• 金额: $ 19.01万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173201
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animals; Antigens; B-Lymphocytes; Body cavities; Chimeric Proteins; Computer Retrieval of Information on Scientific Projects Database; Disease; Funding; Grant; Growth Factor; Homologous Gene; Human; Human Herpesvirus 8; Hyperplasia; Immune response; Infection; Institution; Interleukin-6; Kaposi Sarcoma; Lymphoma; Macaca mulatta; Malignant Neoplasms; Mediating; Nonsense Mutation; Open Reading Frames; Pathogenesis; Patients; Recombinants; Research; Research Personnel; Resources; Rhadinovirus; Role; SIV; Source; Testing; United States National Institutes of Health; Vaccination; Viral; Viral Pathogenesis; Virus Diseases; base; body cavity; effusion; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies in rhesus macaques (RM) reveal that animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus rhadinovirus (RRV), the homologue of Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8), develop B cell hyperplasia compared to RM infected with SIV alone. RRV, like KSHV, encodes an interleukin-6 (IL-6) homologue. The KSHV IL-6 homologue is thought to be a necessary growth factor for Kaposi's sarcoma and the B cell-derived malignancy referred to as body cavity-based lymphomas or primary effusion lymphoma in AIDS patients also infected with KSHV. The long-term objectives of this study aim to evaluate the role of the RRV IL-6 homologue in viral-mediated B cell hyperplasia in the context of an SIV infection. To address this we have developed two strategies. The first strategy involves creation of recombinant RRV that lacks the ability to express vIL-6. A recombinant RRV encoding nonsense mutations in the vIL-6 open reading frame has been created and is currently being characterized. Once characterized, this recombinant will be used to test whether vIL-6 is required for viral mediated pathogenesis. The second strategy involves vaccination of animals with a recombinant vIL-6-human Fc fusion protein as an antigen to induce an immune response against vIL-6. Our preliminary studies indicate that animals inoculated with the vIL-6 fusion protein and adjuvant develop a robust humoral response against vIL-6 capable of neutralizing vIL-6 activity. Challenge infection studies are currently underway and preliminary studies suggest the humoral response is capable of mitigating viral pathogenesis in the SIV-infected RM.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对恒河猴（RM）的研究表明，与仅感染SIV的RM相比，实验性感染猴免疫缺陷病毒（SIV）和恒河猴鼻状病毒（RRV）（卡波西肉瘤相关疱疹病毒（KSHV）/人类疱疹病毒8（HHV-8）的同源物）的动物发生B细胞增生。与KSHV一样，RRV编码白细胞介素-6（IL-6）同源物。 KSHV IL-6同源物被认为是卡波西肉瘤和B细胞衍生的恶性肿瘤（称为也感染KSHV的AIDS患者中的体腔淋巴瘤或原发性渗出性淋巴瘤）的必要生长因子。 本研究的长期目标旨在评价SIV感染时RRV IL-6同系物在病毒介导的B细胞增生中的作用。 为了解决这个问题，我们制定了两项战略。第一种策略涉及产生缺乏表达vIL-6能力的重组RRV。已经创建了在vIL-6开放阅读框中编码无义突变的重组RRV，目前正在对其进行表征。一旦表征，该重组体将用于测试病毒介导的发病机制是否需要vIL-6。第二种策略涉及用重组vIL-6-人Fc融合蛋白作为抗原接种动物以诱导针对vIL-6的免疫应答。我们的初步研究表明，接种vIL-6融合蛋白和佐剂的动物产生了强大的抗vIL-6的体液应答，能够中和vIL-6的活性。目前正在进行攻毒感染研究，初步研究表明体液应答能够减轻SIV感染RM的病毒发病机制。