EARLY GENES OF KAPOSI'S SARCOMA ASSOCIATED HERPESVIRUS

卡波西肉瘤相关疱疹病毒（KSHV），也称为人类 疱疹病毒-8（HHV-8）是γ-疱疹病毒家族成员， 典型地在淋巴细胞中建立潜伏感染。再活化 KSHV从潜伏感染的淋巴储库中裂解感染的可能性似乎是 卡波西肉瘤（KS）发展中的必要先行步骤， 原发性渗出性淋巴瘤（PEL）。因此，病毒从潜伏 裂解周期感染可能不仅对病毒繁殖很重要， 对病毒的致病性也至关重要。调查人员的实验室已经 对KSHV从潜伏期到裂解生命周期的转变感兴趣， 最近在他们的实验室中鉴定了KSHV立即早期（IE）基因（Zhu 等人，1999，附录A）。病毒IE基因通常编码调节蛋白 启动和控制生产性裂解循环感染过程。的 本项目的长期目标是了解 KSHV的再激活及其在病毒致病性中的作用。这项建议会 重点关注KSHV的两个主要的立即早期蛋白，即ORF 50和ORF 45。 重点将放在调节宿主-病毒相互作用的这些 两种IE蛋白质。(1)ORF 50是一种 已知能够激活病毒裂解基因的转录激活因子。在 在拟议的研究中，研究人员将研究ORF 50在 改变宿主细胞基因表达和细胞生理学。(2)ORF 45是 发现与细胞干扰素调节因子-7（IRF-7）相互作用。IRF-7 是转录调节因子，负责激活干扰素 基因对病毒感染的反应。他们将研究ORF 45是否是一种 KSHV用来靶向宿主抗病毒防御的策略。 (3)最后，ORF 50和ORF 45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， (EGS)研究人员将研究ORF 50和ORF 45在KSHV中的作用 裂解性复制和致病性。此外，建议的结果 研究将提供评估是否针对KSHV IE蛋白 （尤其是ORF 50）可能是治疗性干预的新策略。 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.