RHESUS HHV8 HOMOLOGUE IN AIDS-RELATED MALIGNANCIES

艾滋病相关恶性肿瘤中的恒河猴 HHV8 同源物

• 批准号: 8173176
• 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/8173176
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Animal Model; Animals; B-Lymphocytes; Bacterial Artificial Chromosomes; CD 200; Cell Culture Techniques; Computer Retrieval of Information on Scientific Projects Database; Disease; Fibroblasts; Funding; Grant; Growth; Homologous Gene; Human Herpesvirus 8; Hyperplasia; Infection; Institution; Laboratories; Lead; Lymphatic Diseases; Lymphoproliferative Disorders; Macaca mulatta; Multicentric Angiofollicular Lymphoid Hyperplasia; Non-Hodgkin' s Lymphoma; Nonsense Mutation; Open Reading Frames; Pathogenesis; Patients; Recombinants; Research; Research Personnel; Resources; Rhadinovirus; SIV; Source; United States National Institutes of Health; Viral; Viral Load result; Virus; macromolecule; success; viral interferon regulatory factor

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. My laboratory is utilizing the simian immunodeficiency virus (SIV)/rhesus rhadinovirus (RRV)/rhesus macaque (RM) animal model to elucidate how RRV is able to recapitulate many of the lymphoproliferative disorders (LPD) that human herpesvirus 8 (HHV8) is capable of inducing in AIDS patients. These include multicentric Castleman's disease (MCD) and non-Hodgkin's lymphoma (NHL). During the past year we have made significant progress, building upon our success with the infectious and pathogenic rhesus rhadinovirus bacterial artificial chromosome (BAC). This RRV-BAC produces infectious virus (BAC-derived virus) in transfected rhesus fibroblasts that is capable of inducing B cell hyperplasia in SIV-infected RM. More importantly, SIV-infected RM experimentally infected with the BAC-derived virus develops persistent lymphadenopathy, much like wild-type RRV infection. These are important and essential studies which will lead to the identification of viral determinants of pathogenesis. Our initial focus has been on those viral ORFs and macromolecules that are conserved between HHV8 and RRV. These include the viral interferon regulatory factors (vIRFs), viral CD200 (vCD200) homologue and the viral encoded miRNAs. To this end, we have created three recombinants that lack the ability to express these specific viral ORFs. The recombinant lacking the eight vIRFs is capable of growth in cell culture, but is unable to replicate in experimentally infected animals. The second recombinant contains a nonsense mutation in the vCD200. This recombinant grows well in cell culture and is capable of establishing a persistent infection in animals. Interestingly, these animals have higher viral loads than animals infected with wild-type virus and present with RRV-associated disease.

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。 我的实验室正在利用猴免疫缺陷病毒（SIV）/恒河猴Rhadinovirus（RRV）/恒河猴（RM）动物模型，以阐明RRV是如何能够重演许多淋巴组织增生性疾病（LPD），人类疱疹病毒8（HHV 8）是能够诱导艾滋病患者。这些包括多中心Castleman病（MCD）和非霍奇金淋巴瘤（NHL）。 在过去的一年中，我们取得了重大进展，建立在我们的成功与传染性和致病性恒河猴rhadinovirus细菌人工染色体（BAC）。该RRV-BAC在转染的恒河猴成纤维细胞中产生感染性病毒（BAC衍生病毒），其能够在SIV感染的RM中诱导B细胞增生。更重要的是，SIV感染的RM实验性感染BAC衍生的病毒发展为持续性淋巴结病，很像野生型RRV感染。这些都是重要和必要的研究，将导致确定病毒的致病决定因素。我们最初的重点是那些病毒的ORF和大分子之间的HHV 8和RRV的保守。这些包括病毒干扰素调节因子（vIRF）、病毒CD 200（vCD 200）同源物和病毒编码的miRNA。为此，我们创建了三个缺乏表达这些特定病毒ORF的能力的重组体。缺乏八个vIRF的重组体能够在细胞培养中生长，但不能在实验感染的动物中复制。第二个重组体在vCD 200中含有无义突变。该重组体在细胞培养物中生长良好，并且能够在动物中建立持续感染。有趣的是，这些动物的病毒载量高于感染野生型病毒并出现RRV相关疾病的动物。