CMV VECTOR DESIGN AND DEVELOPMENT

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。 该项目是盖茨基金会和国际艾滋病疫苗倡议(IAVI)赞助的艾滋病疫苗开发大型联盟的一部分。该联盟的一个主要目标是利用恒河猴模型开发艾滋病疫苗的新方法，以评估有效性，特别是比较相同挑战方案中所有方法的有效性。本项目的具体目标是设计、构建和测试经过免疫原性和安全性优化的基因缺失的RhCMV载体，然后在为整个联盟制定的标准疗效方案中对野生型和基因缺失的RhCMV载体进行比较评估。将使用DNA和腺病毒载体作为异源启动子或Boost，单独测试RhCMV载体以及在异源启动子-Boost协议中进行测试。该项目支持了RhCMV/SIV载体的第二个大型疗效试验，并证实了它们在系统性进行性感染之前完全控制粘膜给药的高致病性SIV感染的能力。此外，在这笔赠款的赞助下，我们寻求开发减毒CMV载体，以保持免疫原性和有效性，但导致疾病的能力较小。我们已经确定了几个具有前景的特征的候选药物，这些候选药物正在进行正式的安全性和有效性试验。设计具有卓越安全性的CMV载体的工作导致了CMV病理生物学中的一些基本发现，特别是US2-11基因产物介导的CMV下调MHC的生物学作用，如下面的出版物所示。

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. This project is part of a large consortium on AIDS vaccine development sponsored by the Gates Foundation and the International AIDS Vaccine Initiative (IAVI). A major goal of the consortium is to develop new approaches to AIDS vaccine using the rhesus macaque model to assess efficacy and in particular compare efficacy of all approaches in an identical challenge protocol. The specific goal of this project is to design, construct and test gene-deleted RhCMV vectors that have been optimized for immunogenicity and safety, and then comparatively assess both wildtype RhCMV vectors and gene-deleted RhCMV vectors in the standard efficacy protocol developed for the entire consortium. RhCMV vectors will be tested alone as well as in heterologous prime-boost protocols using DNA and adenovirus vectors as the heterologous prime or boost. This project has supported a second large efficacy trial of RhCMV/SIV vectors and has confirmed their ability to completely control mucosally-administered highly pathogenic SIV infection prior to systemic progressive infection. Moreover, under the auspices of this grant, we seek to develop attenuated CMV vectors that maintain immunogenicity, and efficacy, but have less capacity to cause disease. We have identified several candidates with promising characteristics that are being moved forward to formal safety and efficacy trials. Work to design CMV vectors with superior safety profiles has led to a number of basic discoveries in CMV pathobiology, in particular the biologic role of the US2-11 gene product-mediated MHC down-regulation by CMV, as indicated in the publication below.