INFECTION & IMMUNE RESPONSES TO A? HUMAN RETROVIRUS XMRV IN MACAQUES

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本方案的目的是记录人类XMR病毒是否能够在接近人类的模型（即恒河猴）中复制。如果XMRV能够诱导活动性感染，那么该模型中的病毒动力学、传播和抗病毒免疫应答是什么？在前列腺肿瘤患者中，与新鉴定的MuLV相关的γ逆转录病毒感染之间存在强相关性，该患者表现出与I型IFN抗病毒机制相关的RNASEL途径（R462 Q）的遗传失活。因此，假设在RNASEL或潜在的其他选择先天性抗病毒途径缺陷的患者中感染XMR病毒可能导致或至少有助于前列腺肿瘤的增加，特别是在年轻患者中。这对健康计划有明显的影响，包括通过输血传播的可能性。该探索性项目将尝试建立体内模型，并生成用作筛选工具的试剂，以确保血液供应的安全性。我们已经表明，XMRV诱导恒河猴持续的临床沉默感染，具有非常低的病毒血症，可能在免疫/免疫激活后重新激活。在慢性期，在大多数生殖器官和淋巴组织中也观察到病毒复制的证据，表明可能通过性接触传播。这将在新的动物中进行测试，这要归功于新的资金来源以及XMRV在前列腺中的作用，其中早期感染似乎有所增加。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The aims of this protocol are to document whether the human XMR virus is able to replicate in a model close to man, i.e. rhesus macaque. If XMRV is able to induce an active infection, what are the viral kinetics, dissemination and antiviral immune responses in this model. A strong correlation has established between the infection with a newly identified gammaretrovirus related to MuLV in prostate tumors from patients exhibiting a genetic inactivation of the RNASEL pathway (R462Q) linked to type I IFN antiviral mechanism. Thus, the hypothesis is that infection with the XMR virus in patients with a deficiency in the RNASEL or potentially other select innate antiviral pathway may lead to or at least contribute to rise of prostate tumors, especially in younger patients. This has obvious health program consequences including the potential for transmission via blood transfusion. This exploratory project will attempt to set up an in vivo model as well as generate reagents for use as screening tools for ensuring the safety of the blood supply. We have shown that XMRV induces a persistent clinically silent infection in rhesus macaques with very low viremia that may be reactivated following immunization/immune activation. Evidence for viral replication was also seen during the chronic phase in most reproductive organs and lymphoid tissues, suggesting likely transmission via sexual contact. This will be tested in new animals thanks to a new source of funding as well as the role of XMRV in the prostate in which early infection appears enriched.