Viral and cellular gene regulation during lytic KSHV replication

描述（由申请人提供）：本申请的广泛、长期目标是了解卡波西氏肉瘤相关疱疹病毒（KSHV/HHV-8）的调控蛋白如何在裂解复制过程中控制病毒和细胞基因表达。裂解基因产物可能在KSHV的发病机制中发挥作用，有助于KSHV感染细胞和邻近细胞增殖、存活和避免免疫反应的能力。因此，了解裂解基因表达调控的机制与KSHV相关的发病机制有关，KSHV发病机制仍然是发病和死亡的重要原因，特别是在艾滋病毒和KSHV感染率高的地区。KSHV的ORF57蛋白在KSHV复制的早期表达，是疱疹病毒蛋白家族的成员，在疱疹病毒复制中起重要作用。ORF57具有独特的调控特性，可在转录后增强许多无内含子基因的表达。此外，ORF57还能增强特定细胞基因的表达。ORF57可能通过物理结合mRNA并调节其稳定性和核输出来发挥其许多作用。ORF57影响RNA加工的机制以及它的特异性作用是如何确定的，目前还不清楚。因此，我们提出了三个综合目标来研究ORF57在KSHV生物学中的作用。在第一个目标中，我们将定义ORF57结合mRNA的机制以及如何确定ORF57的特异性。在第二个目标中，我们将确定对ORF57功能很重要的主要细胞蛋白，特别是在核输出和mRNA加工方面。在第三个目标中，我们将利用分子遗传学确定ORF57的哪些功能对KSHV复制至关重要。我们还将确定ORF57对内皮细胞和B淋巴细胞基因表达的特异性影响。KSHV是一种与癌症的发展有关的病毒，特别是在那些免疫系统较弱的人身上，比如艾滋病毒感染者。研究病毒如何繁殖对于了解它如何影响被感染的细胞并将其转化为肿瘤细胞非常重要。这类研究也有可能确定针对这种病毒的新药的靶标，从而有助于预防或治疗感染。

DESCRIPTION (provided by applicant): The broad, long term objective of this application is to understand how regulatory proteins of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) control viral and cellular gene expression during lytic replication. Lytic gene products are likely to have a role in pathogenesis of KSHV, contributing to the ability of KSHV-infected cells and adjacent cells to proliferate, survive and avoid immune responses. Understanding the mechanisms by which lytic gene expression is regulated is therefore relevant to KSHV- related pathogenesis which continues to be a significant cause of morbidity and mortality, particularly in areas with high endemic rates of HIV and KSHV infection. The ORF57 protein of KSHV is expressed early during KSHV replication and is a member of a family of herpesvirus proteins that plays an essential role in herpesvirus replication. ORF57 has unique regulatory properties, post-transcriptionally enhancing expression of many intronless genes. In addition, ORF57 enhances expression of specific cell genes. ORF57 is likely to exert many of its effects by physically binding to mRNA and modulating its stability and nuclear export. Much remains unknown about the mechanisms by which ORF57 affects RNA processing and how its specificity of action is determined. We therefore propose three integrated aims to investigate the role of ORF57 in KSHV biology. In the first aim, we will define the mechanisms by which ORF57 binds mRNA and how ORF57 specificity is determined. In the second aim, we will identify the major cellular proteins that are important for ORF57 function, especially with regard to nuclear export and mRNA processing. In the third aim, we will determine which functions of ORF57 are essential for KSHV replication using molecular genetics. We will also determine the specific effects of ORF57 on gene expression in endothelial cells and B lymphocytes. KSHV is a virus that is linked to the development of cancer, particularly in those people who have weakened immune systems, such as those with HIV infection. Studying how the virus reproduces is important to understand how it affects the cells it infects and converts them to tumor cells. Such studies also have the potential to identify targets for new drugs against the virus that may help prevent or treat infection.