FOAMY VIRUS VECTOR FOR IMMUNODEFICIENCY VIRUSES THERAPY

目前可用的用于基因治疗的逆转录病毒载体是基于鼠的。 和鸟类逆转录病毒。灵长类动物原代转基因效率的研究 这些载体对细胞的作用非常低，功能性载体最终 迷路了因此，新的基因治疗方法，以打击艾滋病毒感染 将由于效率低下的交付系统而受到限制。从灵长类开始 逆转录病毒在灵长类细胞中有效复制， 逆转录病毒载体将是抗病毒治疗较好系统 艾滋病毒感染。灵长类泡沫病毒具有几个固有特征， 使它们成为灵长类动物基因转移的理想选择。泡沫病毒是 逆转录病毒的马病毒亚科成员。泡沫病毒是 在包括灵长类在内的许多哺乳动物中发现。这些病毒似乎 在其天然宿主中是非致病性的，尽管病毒广泛存在于 分布在动物体内，并已从几个器官中回收， 组织，包括脑和外周血白细胞。还有，泡沫 就细胞类型而言，病毒在细胞培养物中具有广泛的宿主范围 并且可以在细胞如上皮细胞和 成纤维细胞以及淋巴样细胞和神经细胞。泡沫病毒 从一个物种分离也可以感染其它哺乳动物物种。因此，在本发明中， 泡沫病毒为开发病毒载体提供了独特的机会 系统将基因传递到许多物种的几种细胞类型中。 最近，猴泡沫病毒1型（SFV-1）的基因组 主要研究者已对猕猴进行了分子表征。 该提案的目标是开发一种基于SFV的逆转录病毒载体， 用于抗猴免疫缺陷病毒（SIV）的抗病毒治疗 感染 具体目的1：建立包装细胞系，并将SFV-1 将构建具有选择标记（新霉素）的载体。 具体目的2：将在灵长类动物中测试SFV-1载体的功效。 组织培养细胞系和原代细胞，重点是骨髓 细胞 特异性目的3：将含有SIV的多个核酶的SFV-1载体用于SIV的研究。 构建和多个核酶的抗病毒活性将是 测试. 在病毒基因组中具有多个靶点的核酶预计将被 SIV复制的有效抑制剂。实验结果从这些 研究将有助于使用有效载体的基于核酶的治疗装置 预防艾滋病毒感染系统。

Current available retroviral vectors for gene therapy are based on murine and avian retroviruses. The efficiency gene transfers in primate primary cells by these vectors is very low and functional vectors are eventually lost. Therefore, novel gene therapy approaches to combat HIV infection will be limited as a result of inefficient delivery system. Since primate retroviruses replicate efficiently in primate cells a primate based retroviral vector will be a better system for antiviral therapy against HIV infection. Primate foamy viruses have several inherent features that make them ideal for gene transfer in primates. The foamy viruses are members of the spumaviriniae sub-family of retroviruses. Foamy viruses are found in many mammalian species including primates. These viruses appear to be non-pathogenic in their natural host even though virus is widely distributed in an animal and has been recovered from several organs and tissues including brain and peripheral blood leukocytes. Also, foamy viruses have a broad host range in cell culture with respect to cell type and species and can be propagated in cells such as epithelial and fibroblast cells as well as lymphoid cells and neural cells. A foamy virus isolate from one species can also infect other mammalian species. Thus, foamy viruses offer unique opportunities for developing viral vector systems to deliver genes into several cell types of many species. Recently, the genome of simian foamy virus type l (SFV-l) from rhesus macaque has been molecularly characterized by the Principal Investigator. The goal of this proposal is to develop a retroviral vector based on SFV- l for antiviral therapy against simian immunodeficiency virus (SIV) infection. SPECIFIC AIM 1: Packaging cell lines will be established, and SFV-l vectors with a selectable marker (neomycin) will be constructed. SPECIFIC AIM 2: The efficacy of SFV-l vectors will be tested in primate tissue culture cell lines and primary cells with emphasis on bone marrow cells. SPECIFIC AIM 3: SFV-l vector containing multiple ribozymes for SIV will be constructed and the antiviral activity of the multiple ribozymes will be tested. Ribozymes with multiple targets in the viral genome are expected to be effective inhibitors of SIV replication. Experimental outcomes from these studies will help device ribozyme based therapy with efficient vector system that prevent HIV infection.