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

这个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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 该协议的目的是记录人类XMR病毒是否能够在与人类接近的模型中复制，即恒河猴。如果XMRV能够诱导活动性感染，那么该模型中的病毒动力学、传播和抗病毒免疫反应如何。在前列腺癌患者中感染一种与MuLV相关的新发现的伽玛逆转录病毒之间有很强的相关性，这些患者表现出与I型干扰素抗病毒机制有关的RNASEL途径(R462Q)的遗传失活。因此，假设感染XMR病毒的患者存在RNASE L缺陷或潜在的其他选择的先天抗病毒途径，可能会导致或至少导致前列腺癌的增加，特别是在年轻患者中。这具有明显的健康项目后果，包括通过输血传播的可能性。这一探索性项目将尝试建立体内模型，并产生试剂作为筛查工具，以确保血液供应的安全。我们已经证明，XMRV在病毒血症非常低的恒河猴中诱导了一种持续的临床静止性感染，这种感染可能在免疫/免疫激活后重新激活。在大多数生殖器官和淋巴组织的慢性期也发现了病毒复制的证据，这表明可能通过性接触传播。这将在新的动物身上进行测试，这要归功于新的资金来源以及XMRV在前列腺癌中的作用，在前列腺癌中，早期感染似乎更加丰富。

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.