CMV VECTOR DESIGN AND DEVELOPMENT

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 中心，不一定是研究者的机构。 该项目是由盖茨基金会和国际艾滋病疫苗倡议赞助的艾滋病疫苗开发大型联合会的一部分。 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，以评估效力，特别是比较所有方法在相同攻击方案中的效力。 本项目的具体目标是设计、构建和测试基因缺失的RhCMV载体，这些载体已针对免疫原性和安全性进行了优化，然后在为整个联盟开发的标准有效性方案中比较评估野生型RhCMV载体和基因缺失的RhCMV载体。 将单独测试RhCMV载体，以及使用腺病毒和腺相关病毒（AAV）载体作为异源初免或加强的异源初免-加强方案。 因此，该项目将有三个“活动”。 在活动#1（“CMV载体设计和开发”）中，我们将1）构建和评估缺乏一个或多个“非必需”宿主调节/免疫逃避基因的RhCMV突变体，2）设计和构建能够同时表达多个SIV基因的表达插入物（和载体）以及允许通过施用外部药物（例如，载体，其生长依赖于高生物利用度的药物如多西环素或被其终止），3）提供在作为第一或第二功效试验的一部分施用这些载体的猴中RhCMV载体感染的病毒学和病理学评估（见下文），和4）开发和构建类似于最佳RhCMV设计的人巨细胞病毒（HCMV）的减毒/修饰突变体。 在活动#2中，我们将评估“野生型”RhCMV载体的免疫原性、病理生物学和保护功效，有或没有腺病毒（Ad）5加强。在活动#3中，我们将评估减毒（基因修饰或基因缺失）RhCMV载体的免疫原性、病理生物学和保护功效，有或没有AAV引发。

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. 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 adenovirus and adeno-associated viral (AAV) vectors as the heterologous prime or boost. Thus this project will have 3 "Activities". In Activity #1 ("CMV Vector Design and Development"), we will 1) construct and evaluate RhCMV mutants that lack one or more "non-essential" host modulation/immune evasion genes, 2) design and construct expression inserts (and vectors) capable of simultaneous expression of multiple SIV genes and "safety" inserts that will allow in vivo control of vector replication with administration of an external drug (e.g., vectors whose growth is either dependent on or terminated by a drug of high bioavailability such as doxycycline), 3) provide virologic and pathologic assessment of RhCMV vector infections in the monkeys administered these vectors as part of the first or second efficacy trials (see below), and 4) develop and construct an attenuated/modified mutant of human cytomegalovirus (HCMV) analogous to the optimal RhCMV design. In Activity #2, we will assess the immunogenicity, pathobiology and protective efficacy of "wildtype" RhCMV vectors, with or without Adenovirus (Ad) 5 Boosting. In Activity #3, we will assess the immunogenicity, pathobiology and protective efficacy of attenuated (gene-modified or gene-deleted) RhCMV vectors, with or without AAV priming.