Effects of 1,8-diaminooctane on the FIV Rev regulatory system
Effects of 1,8-diaminooctane on the FIV Rev regulatory system
复制标题
DOI：
10.1006/viro.2002.1659
复制
发表时间：
2002-12-05
期刊：
影响因子：
3.7
通讯作者：
Phillips, TR
中科院分区：
文献类型：
--
作者：
Hart, RA;Billaud, JN;Phillips, TR
REV调节系统的正常功能对于慢病毒的复制至关重要，慢病毒包括猫免疫缺陷病毒(FIV)和人类免疫缺陷病毒1型(HIV-1)。具体来说，REV影响病毒mRNAs的整体稳定性，这些mRNAs编码必要的结构和酶蛋白。反过来，真核生物启动因子(ELF-5A)是REV功能所必需的，也是已知的唯一具有生物活性的蛋白质，其生物活性形式需要唯一的氨基酸--苏氨酸。由于1，8-二氨基辛烷通过破坏细胞内脱氧亚硫氨酸合成酶来阻断亚精氨酸的形成，从而阻止ELF-5A的激活，因此我们研究了1，8-二氨基辛烷对转录后调控的影响。这是第一个证明二氨基辛烷以剂量依赖的方式显著减少病毒复制的结果，即使在接触抑制的条件下也是如此，从而减弱了化合物对细胞增殖的影响。同样，增加二氨基辛烷浓度导致依赖于REV的CAT系统的表达减少，而不影响REV不依赖的CAT系统。在RNA水平上，长期感染的CrFK细胞暴露于浓度增加的二氨基辛烷中，显著降低了未剪接和单剪接病毒mRNAs的水平，并增加了细胞质中多重剪接转录本的相对数量。这项研究的发现是第一次证明FIV，类似于HIV-1，需要ELF-5A来实现有效的REV功能，并且小分子干预可以间接地针对这种慢病毒调控系统。(C)2002年埃尔塞维尔科学公司(美国)。
Proper function of the Rev regulatory system is essential for the replication of lentiviruses, including feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1). Specifically, Rev affects the overall stability of viral mRNAs that encode necessary structural and enzymatic proteins. In turn, the eukaryotic initiation factor (elF-5A) is indispensable for Rev function and is the only known protein whose biologically active form requires the unique amino acid, hypusine. Because 1,8-diaminooctane blocks the formation of hypusine by disrupting the cellular enzyme, deoxyhypusine synthase, thereby preventing activation of elF-5A, we investigated the effects of 1,8-diaminooctane on posttranscriptional regulation. These are the first results to demonstrate that diaminooctane significantly reduced viral replication in a dose-dependent manner, even under conditions of contact inhibition, diminishing the compound's effect on cell proliferation. Similarly, the addition of increased concentrations of diaminooctane caused a reduction in the expression of a Rev-dependent CAT system without affecting a Rev-independent CAT system. At the RNA level, exposure of chronically infected CrFK cells to increasing concentrations of diaminooctane substantially decreased the levels of unspliced and singly spliced viral mRNAs and increased the relative amounts of multiply spliced transcripts in the cytoplasm. The findings of this study are the first demonstration that FIV, similar to HIV-1, requires elF-5A for efficient Rev function and that small molecule intervention can indirectly target this lentivirus regulatory system. (C) 2002 Elsevier Science (USA).