Regulation of Gammaherpesviral Late Gene Expression

 描述（由申请方提供）：疱疹病毒在人群中流行，并引起广泛的危及生命的疾病。β-疱疹病毒（β-HV）和γ-疱疹病毒（γ-HV）亚家族的成员在免疫功能低下的个体中是非常有问题的，导致严重的先天性疾病和各种癌症。在疱疹病毒复制周期中，病毒基因以有序级联的方式在时间上表达，时间与适当的生命周期阶段需求相关。病毒基因组复制后，一组称为晚期基因（L）的病毒基因被强烈激活，并产生子代病毒体组装和外出所必需的蛋白质。β-HV和γ-HV中L基因表达的调控机制在很大程度上仍然是一个谜。然而，揭示疱疹病毒生物学的这一方面已经成为一个高度优先事项，部分原因是最近的发现表明，在这个最终的病毒转录级联受损的突变体不能产生后代病毒粒子。因此，了解L基因转录的关键调控特征可能会揭示抗病毒策略的新靶点。我们的数据表明，晚期基因转录调控是独特的，因为它结合了分子模拟和选择性招募的关键宿主转录机制的方式没有以前观察到的病毒或宿主基因表达。因此，这项资助的重点是定义这种新型基因表达复合物的组成和调控，以及揭示它如何在感染细胞中全面影响基因表达。

 DESCRIPTION (provided by applicant): Herpesviruses are endemic within the human population, and cause a wide range of life-threatening diseases. Members of the beta-herpesvirus (β-HV) and gamma-herpesvirus (γ-HV) subfamilies are extremely problematic in immunocompromised individuals, leading to severe congenital disorders and a variety of cancers. During the herpesviral replication cycle, viral genes are expressed temporally in an ordered cascade, with timing linked to appropriate life cycle stage needs. Following viral genome replication, a group of viral genes termed late genes (L) are robustly activated and produce proteins necessary for progeny virion assembly and egress. Mechanisms governing L gene expression in the β-HV and the γ-HV largely remain a mystery. However, shedding light on this aspect of herpesviral biology has become a high priority, in part due to recent discoveries demonstrating that mutants impaired in this final viral transcription cascade cannot produce progeny virions. An understanding of the regulatory features critical for L gene transcription may therefore reveal robust new targets for antiviral strategies. Our data demonstrate that late gene transcriptional regulation is unique, as it incorporates both molecular mimicry and selective recruitment of key host transcriptional machinery in a manner not previously observed in viral or host gene expression. Thus, the focus of this grant is to define the composition and regulation of this novel gene expression complex, as well as reveal how it may globally impact gene expression in infected cells.