Poeschla E M, Wong-Staal F, Looney D J
Department of Medicine, University of California San Diego, La Jolla 92093-0655, USA.
Nat Med. 1998 Mar;4(3):354-7. doi: 10.1038/nm0398-354.
The molecular bases for species barriers to lentiviral replication are not well understood, but are of interest for explaining lentiviral pathogenesis, devising therapeutic strategies, and adapting lentiviruses to gene therapy. HIV-1-based lentiviral vectors efficiently transduce nondividing cells, but present complex safety concerns. Nonprimate (ungulate or feline) lentiviruses might provide safer alternatives, but these viruses display highly restricted tropisms, and their potential for adaptation as replication-defective vectors capable of transducing human cells is unknown. Feline immunodeficiency virus (FIV) does not infect humans or other non-Felidae despite prevalent natural exposure. Although long terminal repeat (LTR)-directed FIV expression was found to be negligible in human cells, promoter substitution enabled an env-deleted, three-plasmid, human cell-FIV lentiviral vector system to express high levels of FIV proteins and FIV vectors in human cells, thus bypassing the hazards of feline vector producer cells. Pseudotyped FIV vectors efficiently transduced dividing, growth-arrested, and postmitotic human targets. The experiments delineate mechanisms involved in species-restricted replication of this lentivirus and show that human cells support both productive- and infective-phase mechanisms of the FIV life cycle needed for efficient lentiviral vector transduction. Nonprimate lentiviral vectors may offer safety advantages, and FIV vectors provide unique experimental opportunities.
慢病毒复制的物种屏障的分子基础尚未完全明确，但对于解释慢病毒发病机制、制定治疗策略以及使慢病毒适用于基因治疗具有重要意义。基于HIV-1的慢病毒载体能够有效地转导非分裂细胞，但存在复杂的安全问题。非灵长类（有蹄类或猫科）慢病毒可能提供更安全的替代方案，但这些病毒的嗜性高度受限，其作为能够转导人类细胞的复制缺陷型载体的适应潜力尚不清楚。猫免疫缺陷病毒（FIV）尽管自然暴露普遍，但不会感染人类或其他非猫科动物。尽管发现长末端重复序列（LTR）指导的FIV在人类细胞中的表达可忽略不计，但启动子替换使得一种缺失env基因的三质粒人类细胞FIV慢病毒载体系统能够在人类细胞中高水平表达FIV蛋白和FIV载体，从而规避了猫载体生产细胞的风险。假型FIV载体能够有效地转导分裂、生长停滞和有丝分裂后的人类靶细胞。这些实验阐明了这种慢病毒物种限制复制所涉及的机制，并表明人类细胞支持高效慢病毒载体转导所需的FIV生命周期的生产期和感染期机制。非灵长类慢病毒载体可能具有安全优势，而FIV载体提供了独特的实验机会。
