Development of novel therapeutic strategies for AIDS by the molecular regulation strategies for feline immunodeficiency virus infection

为了开发针对猫免疫缺陷病毒（FIV）感染的新型治疗策略，进行了一系列的研究。采用RNA干扰的治疗策略抑制FIV的基因表达。将表达FIV特异性shRNA的质粒载体转染到感染FIV的猫细胞系中，可以一致抑制FIV mRNA/蛋白的表达和逆转录酶的表达。研究了几种cxc趋化因子受体抑制剂（CXCR4拮抗剂）的抗病毒作用。为了提高生物稳定性而合成的c端修饰的CXCR4拮抗剂显示出显著的抑制FIV.3复制的活性。研究了FIV gp40融合相关的七肽重复序列及其衍生物的抗病毒作用。研究发现几种融合肽对不同亚型的FIV病毒株表现出较强的抗病毒作用。为了开发利用树突状细胞（DC）的免疫疗法，我们在多种细胞因子的存在下培养了猫外周血单核细胞。这些细胞显示出树突状突起和DC特有的免疫表型。无症状携带猫感染FIV后，DC功能保持正常。本研究为开发FIV感染的抗病毒治疗提供了创新的发现。在RNA干扰、病毒受体、膜融合和DC方面，猫的FIV感染与人类的艾滋病有显著的相似性；因此，本研究的结果也可用于利用猫系统作为人类艾滋病的动物模型。

A series of studies were performed in order to develop novel therapeutic strategies specific to feline immunodeficiency virus (FIV) infection.1. A therapeutic strategy using RNA interference was employed to inhibit the gene expression of FIV. Transfection of plasmid vectors expressing FIV-specific shRNA into FIV-infected feline cell lines resulted in the consistent suppression of the expression of FIV mRNA/protein and reverse transcriptase.2. Antiviral effect of several types of CXC-chemokine receptor inhibitors (CXCR4 antagonists) was investigated. C-terminal amidated CXCR4 antagonists synthesized to increase the biostability showed a significant activity to inhibit the replication of FIV.3. Antiviral effect of the fusion-associated heptad repeat and its derivatives of FIV gp40 was examined. The study revealed several fusion peptides that showed strong antiviral effect for various FIV strains of different subtypes.4. To develop immunotherapy using dendritic cells (DC), feline peripheral blood monocytes were cultured in the presence of various cytokines. These cells were shown to have dendritic projections and immunological phenotypes characteristic to DC. Function of DC was maintained in asymptomatic carrier cats infected with FIV.The present study provided innovative findings to develop antiviral therapies in FIV infection. With respect to the RNA interference, viral receptor, membrane fusion, and DC, there is a remarkable similarity between FIV infection in cats and AIDS in humans ; thus, the results obtained in this study can be also useful to utilize the feline system as an animal model of AIDS in humans.