DC-BASED FLT3L CO-EXPRESSING AIDS VACCINE

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。 即使在艾滋病毒流行开始25年后，仍然没有有效的艾滋病疫苗。多种疫苗策略(即，病毒样颗粒静脉注射)或DNA质数/载体Boost I.M.)已经被开发出来产生免疫反应，但没有一种能够防止最终的疾病进展。非人灵长类动物模型中的减毒活病毒(live-tenuated SIV，NEF)能诱导针对SIV蛋白的特异性免疫反应，并保护动物免受SIV攻击；然而，病毒复制和致病性与SIV NEF有关。本项目的重点是利用复制缺陷慢病毒载体、共表达免疫调节细胞因子基因、体外转导靶细胞等基因转移技术来改进艾滋病疫苗策略。我们正在开发一系列基于SIV的新型慢病毒载体，在体外高效转导CD34+造血干/祖细胞，在培养中扩增转导细胞，诱导其向专业抗原提呈细胞(如巨噬细胞或树突状细胞)分化，以表达病毒抗原和细胞因子Flt3L。这些转导细胞将用于自体宿主的疫苗接种。将评估接种疫苗的恒河猴的免疫学参数和对SIVmac挑战的保护作用。

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. Even 25 years after the HIV epidemic began, an effective AIDS vaccine is still unavailable. Multiple vaccine strategies (ie, viral-like particles i.v. or DNA-prime/vector boost i.m.) have been developed to generate immune responses, but none have protected from eventual disease progression. The live-attenuated SIV (nef) in non-human primate models has been shown to induce a strong specific immune response against SIV proteins and to protect animals from subsequent SIV challenge; however, viral replication and pathogenicity has been associated with SIV nef. The focus of this project is to amend AIDS vaccine strategies with gene transfer technologies such as using replication defective lentiviral vectors, co-expressing immuno-modulatory cytokine genes, transducing target cells ex vivo. We are developing a new series of SIV-based lentiviral vectors to efficiently transduce CD34+ hematopoietic stem/progenitor cells ex vivo, expand the transduced cells in culture, induce their differentiation to professional antigen presenting cells (like macrophages or dendritic cells), for expression of viral antigens and the cytokine Flt3L. These transduced cells will be used for vaccination of the autologous host. Vaccinated rhesus will be evaluated for immunological parameters and for protection from challenged with SIVmac.