Sauter S L, Gasmi M
GenStar Therapeutics, San Diego, California 92121, USA.
Somat Cell Mol Genet. 2001 Nov;26(1-6):99-129. doi: 10.1023/a:1021078714105.
Why is feline immunodeficiency virus (FIV) such an appealing candidate for gene therapy vector development? Phylogenetic analysis suggests FIV is only distantly related to the primate lentiviruses, and despite repeated exposure, neither seroconversion nor other detectable evidence of human infection occurs. FIV naturally infects diverse Felidae worldwide, including the domestic cat. Here, the disease progression parallels the immunodeficiency caused by HIV, and for that reason, FIV and the cat provide an excellent model for anti-virals and AIDS vaccine research. Simple genome organization also facilitates vector development and analysis: FIV has only three accessory/regulatory proteins. To overcome FIV's cat-specific tropism, feline vectors are equipped with hybrid LTRs, since the FIV LTR shows low activity in human cells. Recombinant FIV vectors generate titers comparable to other lentiviral systems, are capable of incorporating heterologous envelopes and efficiently transduce dividing and nondividing cells in the presence and absence of the accessory proteins in vitro. Compared to HIV vectors, FIV vector development is still in its infancy, but initial in vivo data in various species and tissues indicate long-term gene expression at therapeutic levels, and thus FIV vectors hold great promise. Future efficacy studies in animal models and primates will determine the FIV vectors' suitability for gene therapy. The design of recombinant FIV vectors incorporates safety features described for primate lentiviral vectors with the benefit that biosafety testing of FIV vectors can occur in the natural host. Currently, FIV vectors are generated in a transient fashion, but the availability of a stable producer system amenable to better characterization and scale-up will considerably increase the potential for use of FIV vectors in the clinic.
为什么猫免疫缺陷病毒（FIV）是基因治疗载体开发中如此有吸引力的候选对象呢？系统发育分析表明，FIV与灵长类慢病毒的亲缘关系较远，而且尽管有反复接触，但人类既不会发生血清转化，也没有其他可检测到的感染证据。FIV在全球范围内自然感染包括家猫在内的多种猫科动物。在这里，疾病进展与HIV引起的免疫缺陷相似，因此，FIV和猫为抗病毒药物及艾滋病疫苗研究提供了一个极佳的模型。简单的基因组结构也便于载体的开发和分析：FIV只有三种辅助/调节蛋白。为了克服FIV对猫的特异性嗜性，猫载体配备了杂交长末端重复序列（LTR），因为FIV的LTR在人类细胞中活性较低。重组FIV载体产生的滴度与其他慢病毒系统相当，能够整合异源包膜，并在体外存在和不存在辅助蛋白的情况下有效地转导分裂细胞和非分裂细胞。与HIV载体相比，FIV载体的开发仍处于起步阶段，但在各种物种和组织中的初步体内数据表明，其能在治疗水平上实现长期基因表达，因此FIV载体前景广阔。未来在动物模型和灵长类动物中的疗效研究将确定FIV载体是否适合基因治疗。重组FIV载体的设计融入了灵长类慢病毒载体所具备的安全特性，其好处是FIV载体的生物安全性测试可以在天然宿主中进行。目前，FIV载体是以瞬时方式产生的，但一个易于更好地表征和扩大规模的稳定生产系统的出现，将大大增加FIV载体在临床上应用的潜力。
