Controlling Multicycle Replication of Live-Attenuated HIV-1 Using an Unnatural Genetic Switch.
Controlling Multicycle Replication of Live-Attenuated HIV-1 Using an Unnatural Genetic Switch.
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DOI：
10.1021/acssynbio.6b00373
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发表时间：
2017-04-21
影响因子：
4.7
通讯作者：
Guo J
中科院分区：
文献类型：
--
作者：
Yuan Z;Wang N;Kang G;Niu W;Li Q;Guo J
目前迫切需要一种安全有效的1型人体免疫缺陷病毒（HIV-1）疫苗，但这一疫苗仍然难以找到。虽然HIV-1减毒活疫苗可以提供有效的保护，如在恒河猴-猿猴免疫缺陷病毒模型中所证明的，但与不受控制的病毒复制相关的潜在致病性后果排除了此类疫苗的临床应用。我们研究了一种新的方法来解决这个问题，通过控制减毒活HIV-1复制通过一个非自然的基因开关，是基于琥珀抑制策略。在这里，我们报告了所有在一个活的减毒HIV-1突变体，包含琥珀抑制系统的基因组拷贝的建设。这种基因修饰导致病毒能够在体外进行多循环复制，并且可以使用非天然氨基酸作为线索来打开和关闭。这种独立的、复制可控的减毒HIV-1病毒代表了朝着产生安全有效的减毒活HIV-1疫苗迈出的重要一步。本研究所提出的策略可用于其他减毒活疫苗的开发。
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 multi-cycle 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 towards 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.