StpC-based gene therapy targeting latent reservoirs of HIV-1.
StpC-based gene therapy targeting latent reservoirs of HIV-1.
复制标题
基于 StpC 的基因治疗针对 HIV-1 的潜在储存库。
DOI：
10.1016/j.antiviral.2006.06.010
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发表时间：
2006
影响因子：
7.6
通讯作者：
Henderson,EarlE
中科院分区：
文献类型：
--
作者：
Turner,LorianneStehouwer;Tsygankov,AlexanderY;Henderson,EarlE
HIV-1 形成潜伏病毒库的能力是根除的主要障碍。消除潜伏病毒库的一种方法是诱导疗法，其中含有潜伏病毒的细胞被激活，从而启动病毒复制。我们构建了编码疱疹病毒 saimiri 亚组 C saimiri 转化相关蛋白 (StpC) 的慢病毒载体，该蛋白已被证明可以在巨细胞病毒启动子的控制下调节 HIV-1 复制，以确定 StpC 上调潜在 HIV-1 的能力。我们在 HIV-1 长末端重复序列 (LTR) 启动子的控制下纳入了自杀基因，即单纯疱疹病毒胸苷激酶 (TK)。我们假设，在潜伏感染细胞中 StpC 表达时，诱导病毒复制并随后产生 LTR 病毒反式激活子，从而激活 tk 基因的表达，使细胞对核苷类似物更昔洛韦 (GCV) 敏感。潜伏感染细胞系 J1.1 的转导导致病毒复制增加。当存在 GCV 转导的细胞时，HIV-1 复制减少，细胞增殖受到抑制，细胞凋亡增加。该原型载体证明了基于基因的诱导剂和自杀基因作为针对潜在 HIV-1 储存库的新方法的实用性。
The ability of HIV-1 to form latent reservoirs presents a major obstacle to eradication. One approach to elimination of the latent reservoir is induction therapy, whereby cells harboring latent virus are activated and therefore initiate virus replication. We have constructed a lentiviral vector encoding Herpesvirus saimiri subgroup C saimiri transformation-associated protein (StpC), which has been shown to modulate HIV-1 replication, under the control of a cytomegalovirus promoter in order to determine the ability of StpC to upregulate latent HIV-1. We have included a suicide gene, herpes simplex virus thymidine kinase (TK), under the control of the HIV-1 long terminal repeat (LTR) promoter. We hypothesized that upon StpC expression in latently infected cells induction of virus replication and subsequent production of viral transactivators of the LTR will activate expression of the tk gene, sensitizing the cells to the nucleoside analogue ganciclovir (GCV). Transduction of the latently infected cell line J1.1 resulted in increased virus replication. In the presence of GCV transduced cells exhibited decreased HIV-1 replication, inhibition of cell proliferation, and increased apoptosis. This prototype vector serves as a proof of concept of the utility of gene-based induction agents and suicide genes as a new method for targeting reservoirs of latent HIV-1.