Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan;
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1269-E1278. doi: 10.1073/pnas.1715724115. Epub 2018 Jan 22.
Viruses causing chronic infection artfully manipulate infected cells to enable viral persistence in vivo under the pressure of immunity. Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection mainly in CD4+ T cells in vivo and induces leukemia in this subset. HTLV-1-encoded Tax is a critical transactivator of viral replication and a potent oncoprotein, but its significance in pathogenesis remains obscure due to its very low level of expression in vivo. Here, we show that Tax is expressed in a minor fraction of leukemic cells at any given time, and importantly, its expression spontaneously switches between on and off states. Live cell imaging revealed that the average duration of one episode of Tax expression is ∼19 hours. Knockdown of Tax rapidly induced apoptosis in most cells, indicating that Tax is critical for maintaining the population, even if its short-term expression is limited to a small subpopulation. Single-cell analysis and computational simulation suggest that transient Tax expression triggers antiapoptotic machinery, and this effect continues even after Tax expression is diminished; this activation of the antiapoptotic machinery is the critical event for maintaining the population. In addition, Tax is induced by various cytotoxic stresses and also promotes HTLV-1 replication. Thus, it seems that Tax protects infected cells from apoptosis and increases the chance of viral transmission at a critical moment. Keeping the expression of Tax minimal but inducible on demand is, therefore, a fundamental strategy of HTLV-1 to promote persistent infection and leukemogenesis.
导致慢性感染的病毒巧妙地操纵受感染的细胞，使其在免疫压力下在体内持续存在。人类 T 细胞白血病病毒 1 型（HTLV-1）主要在体内的 CD4+T 细胞中建立持续感染，并在该亚群中诱导白血病。HTLV-1 编码的 Tax 是病毒复制的关键反式激活因子和一种有效的癌蛋白，但由于其在体内的表达水平非常低，其在发病机制中的意义仍不清楚。在这里，我们表明 Tax 在任何给定时间都在一小部分白血病细胞中表达，重要的是，其表达会自发地在开启和关闭状态之间切换。活细胞成像显示，Tax 表达的一个发作的平均持续时间约为 19 小时。Tax 的敲低会迅速诱导大多数细胞凋亡，表明 Tax 对于维持细胞群体至关重要，即使其短期表达仅限于一小部分亚群。单细胞分析和计算模拟表明，短暂的 Tax 表达会触发抗凋亡机制，即使 Tax 表达减少后，这种效应仍会持续；这种抗凋亡机制的激活是维持群体的关键事件。此外，Tax 可被各种细胞毒性应激诱导，并且还可促进 HTLV-1 复制。因此，Tax 似乎可以保护受感染的细胞免于凋亡，并在关键时刻增加病毒传播的机会。因此，保持 Tax 的表达最小化但可按需诱导是 HTLV-1 促进持续感染和白血病发生的基本策略。
