艾滋病已成为全球面临的主要健康卫生问题，传统的联合抗逆转录病毒疗法“鸡尾酒疗法”尽管可以一定程度上控制HIV病程，但是高昂费用、病毒清除不完全和耐药性等问题限制了其疗效，亟需新的治疗方法应对HIV感染。近日，美国NIC和TSRI研究所Pathak团队在Molecular Therapy: Nucleic Acid期刊上发表题为Development of lentiviral vectors for HIV-1 gene therapy with Vif-resistant APOBEC3G的论文，研究利用抗Vif抗性的A3G-D128K构建了自激活慢病毒系统，特异性抑制T细胞中HIV复制，同时不易产生抗性突变。该项研究提供了一种潜在的HIV基因治疗方法。
[attach]3067[/attach]
附文献信息：
ABSTRACT
Strategies to control HIV-1 replicationwithout antiviral therapy are needed to achieve a functional cure. To exploitthe innate antiviral function of restriction factor cytidine deaminase APOBEC3G(A3G), we developed self-activating lentiviral vectors that efficiently deliverHIV-1 Vif-resistant mutant A3G-D128K to target cells. To circumvent APOBEC3 expression invirus-producing cells, which diminishes virus infectivity, a vector containingtwo overlapping fragments of A3G-D128K was designed that maintained the gene inan inactive form in the virus-producer cells. However, during transduction of target cells, retroviral recombinationbetween the direct repeats reconstituted an active A3G-D128K in 89-98% of transducedcells. Lentiviral vectors that expressed A3G-D128K transduced CD34+hematopoietic stem and progenitor cells with a high efficiency (>30%). A3G-D128K expression in T cell lines CEM,CEMSS, and PM1 potently inhibited spreading infection of several HIV-1 subtypesby C-to-U deamination leading to lethal G-to-A hypermutation and inhibition ofreverse transcription. SIVmac239 andHIV-2 were not inhibited since their Vifs degraded A3G-D128K. A3G-D128Kexpression in CEM cells potently suppressed HIV-1 replication for >3.5months without detectable resistant virus, suggesting a high genetic barrierfor emergence of A3G-D128K resistance. Taken together, A3G-D128K expression inHIV-1 target cells is potential anti-HIV gene therapy approach that could becombined with other therapies for the treatment and functional cure of HIV-1infection.