INTERACTION OF VZV GENES TRANSCRIBED DURING LATENCY IN HUMAN GANGLIA

人类神经节潜伏期转录的 VZV 基因的相互作用

• 批准号: 6410649
• 负责人: RANDALL J. COHRS
• 金额: $ 24.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410649
• 关键词: ganglion cell; genetic mapping; genetic promoter element; genetic transcription; immunoelectron microscopy; latent virus infection; nervous system infection; neurotropic virus; tissue /cell culture; transfection; varicella zoster virus; virus genetics; virus protein; virus replication

Reactivation of latent varicella zoster virus (VZV) from dorsal root ganglia at all levels of the neuraxis produces serious neurological disease. In latently infected ganglia from normal humans, we have shown that low levels of VZV DNA are present in a circular form, that VZV genes 21, 29, 62 and 63 are transcribed, and that VZV gene 63 is translated. The fact that the VZV gene transcribed during latency include those immediate- early (IE) genes with either proven (gene 62) or implied (gene 63) regulatory functions and genes with putative DNA binding capacity (VZV genes 21 and 29) provides the ratione for our hypothesis that proteins encoded by VZV genes transcribed during latency inhibit virus replication. Synthesis of virus proteins and assembly of infectious virions are complex events that depend on coordinated gene activity and differ during productive infection and latency. For example, IE62 (the product of VZV gene 62) is a potent transactivator of many VZV genes associated with productive infection. While the function of IE63 (the product of VZV gene 63) is still uncertain, it may also function to regulate VZV gene expression and might be pivotal to the programmed switch from IE to early virus gene usage. During latency, however, the transactivation of VZV genes of IE62 or IE63 is modified. For example, in the presence of IE62 and IE63, the promoters for VZV genes 20, 21, 28, and 29 are active, while in latently infected ganglia where genes 62 and 63 are transcribed, the promoters for VZV genes 20 and 28 are silent. Thus, we will examine the hypothesis that IE62 and IE63 transactivation is regulated by VZV gene 21 and 29 proteins. Since the model relies on the translation of the transcripts detected during latency, we will search for proteins encoded by VZV genes 63, 62, 21 and 29 in the same latently infected human ganglionic cell. We will determine whether the VZV gene 21 protein forms a complex with VZV gene 29 protein, and whether this complex can inhibit VZV gene transactivation induced by IE62 or IE63. We will assay VZV replication, virus gene transcription, and virus promoter activity in cell lines expressing VZV genes 21 and 29. Our accumulated data on VZV gene expression in the human ganglia during latency have been assembled into a testable model designed to determine the interaction of these virus proteins. Such information will provide a rationale for future hypotheses about VZV reactivation, a cause of considerable morbidity, and occasional mortality, especially in elderly and immunocompromised humans.

从背根的潜在水痘带状疱疹病毒（VZV）重新激活 神经神经的神经神经神经产生严重的神经系统 疾病。在正常人的潜在受感染的神经节中，我们显示了 低水平的VZV DNA以圆形形式存在，即VZV基因 转录21、29、62和63，并翻译VZV基因63。这 延迟期间转录的VZV基因的事实包括 具有经过证明的（基因62）或隐含的早期（IE）基因（基因63） 具有假定DNA结合能力的调节功能和基因（VZV 基因21和29）为我们的假设提供了蛋白质的理由 在潜伏期抑制病毒复制过程中转录的VZV基因编码。 病毒蛋白的合成和传染性病毒的组装是复杂的 依赖于协调基因活性并且在期间有所不同的事件 生产感染和潜伏期。例如，IE62（VZV的产物 基因62）是许多与之相关的VZV基因的有效反式激活因子 生产感染。而IE63的功能（VZV基因的产物 63）仍然不确定，它也可能功能调节VZV基因 表达，可能是从IE到早期的编程开关关键的 病毒基因使用。但是，在延迟期间，VZV的反式激活 IE62或IE63的基因已修改。例如，在IE62存在的情况下 IE63，VZV基因20、21、28和29的启动子是活跃的，而 在被抄录的基因62和63的潜在感染神经节中， VZV基因20和28的启动子是无声的。因此，我们将检查 IE62和IE63反式激活的假设受VZV基因21调节 和29种蛋白质。由于该模型依赖于翻译 在延迟期间检测到的成绩单，我们将搜索编码的蛋白质 由VZV基因63、62、21和29在同一延迟感染的人中 神经节细胞。我们将确定VZV基因21蛋白是否形成 具有VZV基因29蛋白的复合物，该复合物是否可以抑制 IE62或IE63诱导的VZV基因反式激活。我们将分析VZV 细胞中的复制，病毒基因转录和病毒启动子活性 表达VZV基因21和29的线。我们在VZV基因上的累积数据 潜伏期间人神经节中的表达已被组装成一个 可测试的模型，旨在确定这些病毒的相互作用 蛋白质。这些信息将为未来的假设提供理由 关于VZV重新激活，造成相当大的发病率和偶尔的原因 死亡率，特别是在老年人和免疫功能低下的人类中。