EARLY GENES OF KAPOSI'S SARCOMA ASSOCIATED HERPESVIRUS

卡波西肉瘤相关疱疹病毒，又称人类 疱疹病毒-8(HHV-8)是伽玛-疱疹病毒家族的成员之一。 特征性地在淋巴样细胞中建立潜伏感染。重新激活 潜伏感染淋巴储存库的KSHV裂解感染似乎是一种 Kaposi肉瘤(KS)发生和发展的必要先行步骤 原发性积液淋巴瘤(PEL)。因此，病毒从潜伏状态的切换 裂解循环感染可能不仅对病毒的繁殖很重要，而且 对病毒的致病性也至关重要。调查人员的实验室已经 对KSHV从潜伏期到裂解期的转换感兴趣，以及几个 KSHV即刻早期(IE)基因最近在他们的实验室(朱)被发现 等人，1999，附录A)。病毒IE基因通常编码调节蛋白 启动和控制有效的裂解循环感染过程。这个 这个项目的长期目标是了解 KSHV的重新激活及其在病毒致病中的作用。这项提议将 重点研究KSHV的两个主要的即刻早期蛋白，即ORF50和ORF45。 重点将放在这些因素对宿主-病毒相互作用的调节上 病毒重新激活过程中的两个IE蛋白。(1)ORF50是 已知能够激活病毒裂解基因的转录激活剂。在……里面 在拟议的研究中，研究人员将调查ORF50在 改变宿主细胞的基因表达和细胞生理。(2)ORF45为 发现与细胞干扰素调节因子-7(IRF-7)相互作用。IRF-7 是一种转录调节因子，负责干扰素的激活 对病毒感染作出反应的基因。他们将调查ORF45是否是一种 KSHV用来瞄准宿主抗病毒防御系统组件的策略。 (3)最后，ORF50和ORF45的表达将被特异性阻断 使用一种新的基因失活技术，即外部引导序列 研究人员将研究ORF50和ORF45在KSHV中的作用 裂解复制和致病性。此外，建议的 研究将提供靶向KSHV IE蛋白的评估 (尤其是ORF50)可能成为治疗高血压的新策略。 KSHV相关疾病。

Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is a member of gamma-herpesvirus family, which characteristically establishes latent infection in lymphoid cells. Reactivation of lytic infection of KSHV from latently infected lymphoid reservoir seems a necessary antecedent step in the development of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Therefore, the switch of the virus from latent to lytic cycle infection may be not only important for viral propagation, but also crucial for viral pathogenicity. The investigators' laboratory has been interested in the switch of KSHV from latency to lytic life cycle, and several KSHV immediate early (IE) genes have been recently identified in their lab (Zhu et al, 1999, Appendix A). Viral IE genes usually encode regulatory proteins that initiate and control the productive lytic cycle infection process. The long-term objective of this project is to understand the mechanism of the reactivation of KSHV and its roles in viral pathogenicity. This proposal will focus on two major immediate-early proteins of KSHV, namely ORF50 and ORF45. Emphasis will be placed on the modulation of host-virus interaction by these two IE proteins during the viral reactivation. (1) The ORF50 is a transcriptional activator known to be able to activate viral lytic genes. In the proposed studies, the researchers will investigate the role of ORF50 in altering host cellular gene expression and cell physiology. (2) The ORF45 was found to interact with cellular interferon regulatory factor-7 (IRF-7). IRF-7 is a transcription regulator, which is responsible for activation of interferon genes in response to viral infection. They will investigate whether ORF45 is a strategy that KSHV uses to target components of the host anti-viral defenses. (3) Finally, the expression of ORF50 and ORF45 will be specifically blocked by using a novel gene-inactivation technique, namely the external guide sequence (EGS), and the investigators will examine roles of ORF50 and ORF45 in KSHV lytic replication and pathogenicity. In addition, the results from the proposed studies will provide assessment of whether targeting KSHV IE proteins (especially ORF50) could be new strategies for therapeutic intervention of KSHV-associated diseases.