Yuan Zhe, Wang Nanxi, Kang Guobin, Niu Wei, Li Qingsheng, Guo Jiantao
Nebraska Center for Virology & School of Biological Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska 68583, United States.
Department of Chemistry, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
ACS Synth Biol. 2017 Apr 21;6(4):721-731. doi: 10.1021/acssynbio.6b00373. Epub 2017 Jan 30.
A safe and effective human immunodeficiency virus type 1 (HIV-1) vaccine is urgently needed, but remains elusive. While HIV-1 live-attenuated vaccine can provide potent protection as demonstrated in rhesus macaque-simian immunodeficiency virus model, the potential pathogenic consequences associated with the uncontrolled virus replication preclude such vaccine from clinical applications. We investigated a novel approach to address this problem by controlling live-attenuated HIV-1 replication through an unnatural genetic switch that was based on the amber suppression strategy. Here we report the construction of all-in-one live-attenuated HIV-1 mutants that contain genomic copy of the amber suppression system. This genetic modification resulted in viruses that were capable of multicycle replication in vitro and could be switched on and off using an unnatural amino acid as the cue. This stand-alone, replication-controllable attenuated HIV-1 virus represents an important step toward the generation of a safe and efficacious live-attenuated HIV-1 vaccine. The strategy reported in this work can be adopted for the development of other live-attenuated vaccines.
迫切需要一种安全有效的1型人类免疫缺陷病毒（HIV-1）疫苗，但目前仍难以实现。虽然HIV-1减毒活疫苗在恒河猴-猴免疫缺陷病毒模型中已证明能提供有效保护，但与病毒不受控制的复制相关的潜在致病后果使这种疫苗无法应用于临床。我们研究了一种新方法来解决这个问题，即通过基于琥珀抑制策略的非天然基因开关来控制减毒活HIV-1的复制。在此，我们报告了包含琥珀抑制系统基因组拷贝的一体化减毒活HIV-1突变体的构建。这种基因修饰产生的病毒能够在体外进行多轮复制，并可以使用非天然氨基酸作为信号进行开启和关闭。这种独立的、复制可控的减毒HIV-1病毒代表了朝着开发安全有效的减毒活HIV-1疫苗迈出的重要一步。本研究报道的策略可用于开发其他减毒活疫苗。
