Cellular FLIP can substitute for the herpes simplex virus type 1 latency-associated transcript gene to support a wild-type virus reactivation phenotype in mice.
Cellular FLIP can substitute for the herpes simplex virus type 1 latency-associated transcript gene to support a wild-type virus reactivation phenotype in mice.
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DOI：
10.1080/13550280802216510
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发表时间：
2008-10
影响因子：
3.2
通讯作者：
Wechsler SL
中科院分区：
文献类型：
--
作者：
Jin L;Carpenter D;Moerdyk-Schauwecker M;Vanarsdall AL;Osorio N;Hsiang C;Jones C;Wechsler SL
单纯疱疹病毒1型（HSV-1）的潜伏相关转录物（LAT）缺失突变体具有减少的再活化表型。因此，LAT在HSV-1的潜伏-再活化循环中起着至关重要的作用。我们已经表明，LAT具有抗凋亡活性，并证明了嵌合病毒，dLAT-cpIAP，从替换LAT与杆状病毒抗凋亡基因cpIAP，在小鼠和兔中具有野生型HSV-1再激活表型。因此，LAT可以被替代的抗细胞凋亡基因取代，证实LAT的抗细胞凋亡活性在LAT增强病毒再激活表型的机制中发挥着重要作用。然而，由于cpIAP干扰两种主要的细胞凋亡途径，这些研究没有解决LAT的促再活化表型功能是否是由于阻断外源性（Fas-配体-，caspase-8-或caspase-10-依赖性途径）或内源性（线粒体-，caspase-9-依赖性途径）途径，或是否两种途径都必须被阻断。在这里，我们构建了HSV-1 LAT（−）突变体，其在LAT启动子的控制下表达细胞FLIP（细胞FLICE样抑制蛋白），并取代LAT核苷酸76至1667。小鼠眼部感染这种突变体，命名为dLAT-FLIP，并使用三叉神经节外植体模型确定再活化表型。dLAT-FLIP具有与野生型病毒相似的再活化表型，并且显著高于LAT（-）突变体dLAT 2903。因此，负责增强再活化表型的LAT功能可以被主要阻断外源性信号细胞凋亡途径的抗细胞凋亡基因所取代。
Latency-associated transcript (LAT) deletion mutants of herpes simplex virus type 1 (HSV-1) have reduced reactivation phenotypes. Thus, LAT plays an essential role in the latency-reactivation cycle of HSV-1. We have shown that LAT has antiapoptosis activity and demonstrated that the chimeric virus, dLAT-cpIAP, resulting from replacing LAT with the baculovirus antiapoptosis gene cpIAP, has a wild-type HSV-1 reactivation phenotype in mice and rabbits. Thus, LAT can be replaced by an alternative antiapoptosis gene, confirming that LAT’s antiapoptosis activity plays an important role in the mechanism by which LAT enhances the virus’ reactivation phenotype. However, because cpIAP interferes with both of the major apoptosis pathways, these studies did not address whether LAT’s proreactivation phenotype function was due to blocking the extrinsic (Fas-ligand–, caspase-8–, or caspase-10–dependent pathway) or the intrinsic (mitochondria-, caspase-9–dependent pathway) pathway, or whether both pathways must be blocked. Here we constructed an HSV-1 LAT(−) mutant that expresses cellular FLIP (cellular FLICE-like inhibitory protein) under control of the LAT promoter and in place of LAT nucleotides 76 to 1667. Mice were ocularly infected with this mutant, designated dLAT-FLIP, and the reactivation phenotype was determined using the trigeminal ganglia explant model. dLAT-FLIP had a reactivation phenotype similar to wild-type virus and significantly higher than the LAT(−) mutant dLAT2903. Thus, the LAT function responsible for enhancing the reactivation phenotype could be replaced with an antiapoptosis gene that primarily blocks the extrinsic signaling apoptosis pathway.
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影响因子：
4.8
作者：
Kischkel, FC;Lawrence, DA;Ashkenazi, A
通讯作者：
Ashkenazi, A
影响因子：
3.2
作者：
Jin, Ling;Perng, Guey-Chuen;Wechsler, Steven L.
通讯作者：
Wechsler, Steven L.
影响因子：
3.8
作者：
Mott, KR;Osorio, N;Perng, GC
通讯作者：
Perng, GC
影响因子：
5.4
作者：
Inman, M;Perng, GC;Jones, C
通讯作者：
Jones, C
影响因子：
5.4
作者：
Jin, L;Peng, WP;Wechsler, SL
通讯作者：
Wechsler, SL