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

进行了一系列研究，以开发新的治疗策略，具体到猫免疫缺陷病毒（FIV）感染。采用RNA干扰的治疗策略来抑制FIV的基因表达。将表达FIV特异性shRNA的质粒载体转染FIV感染的猫细胞系，可持续抑制FIV mRNA/蛋白和逆转录酶的表达.研究了几种CXC趋化因子受体抑制剂（CXCR 4拮抗剂）的抗病毒作用。C-末端酰胺化的CXCR 4拮抗剂合成以增加生物稳定性，显示出显著的抑制FIV复制的活性。检测了FIV gp 40的融合相关七肽重复序列及其衍生物的抗病毒作用。本研究筛选出了几种对不同亚型的FIV毒株具有较强抗病毒作用的融合肽.为了开发使用树突状细胞（DC）的免疫疗法，在各种细胞因子的存在下培养猫外周血单核细胞。这些细胞被证明具有树突状突起和DC特有的免疫表型。无症状携带FIV猫的DC功能得以维持。本研究为FIV感染的抗病毒治疗提供了新的发现。关于RNA干扰、病毒受体、膜融合和DC，猫中的FIV感染和人类中的AIDS之间存在显著的相似性;因此，本研究中获得的结果也可用于利用猫系统作为人类中AIDS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.