Deregulation of host functions and persistence of KSHV

描述（由申请人提供）：超过90%的世界人口持续感染几种疱疹病毒。卡波西肉瘤相关疱疹病毒（KSHV）可在口腔中建立持续感染，并可经口传播。KSHV感染表现在艾滋病患者中，并导致几种淋巴组织增生性疾病以及卡波西肉瘤。虽然宿主细胞和免疫系统已经进化出控制疱疹病毒感染的机制，但疱疹病毒也已经发展出逃避和/或拮抗它们的策略。疱疹病毒利用多个病毒基因来实现精确的基因表达控制并抵消宿主免疫系统，这两者对于建立、维持和从潜伏期重新激活都是必不可少的。潜伏期和裂解性复制之间的成功转换对于病毒在宿主中的持久性至关重要。目前还不清楚病毒如何调节其自身的表达和失调细胞转录，以有效地复制和逃避免疫反应。为了了解KSHV持续存在的机制，集中在基因表达调控和免疫逃避的水平上，加州的四个实验室联合起来。本论文主要研究了以下四个方面的问题：1）KSHV ORF 36抑制型干扰素产生的机制（项目负责人：孙仁，UCLA）; 2）ORF 36作为KSHV唯一的病毒激酶的转录调节作用（项目负责人：孔兴坚，加州大学戴维斯分校）; 3）两种KSHV编码的调节剂的潜在机制（ORFI 0和ORF 45）的先天免疫途径（项目负责人，Don Ganem，UCSF）; 4）建立KSHV持续感染的非人灵长类动物模型，以确定ORF 1，ORF 36，体内病毒感染期间的K-bZIPPRF 45和K5 K3（项目负责人：Jae Jung，哈佛/南加州大学）。

DESCRIPTION (provided by applicant): More than 90% of the world population is persistently infected with several herpes viruses. Kaposi's sarcoma-associated herpes virus (KSHV) can establish persistent infection in the oral cavity and can be transmitted orally. KSHV infection manifests in AIDS patients and leads to several lymphoproliferative diseases as well as Kaposi's sarcoma. Although the host cells and the immune system have evolved mechanisms to control herpes viral infections, herpes viruses have also developed strategies to evade and/or antagonize them. Herpes viruses employ multiple viral genes to achieve precise gene expression control and to counteract the host immune system, both of which are essential to establish, maintain, and reactivate from latency. The successful transition between latency and lytic replication is critical for viral persistence in the host. It has not been clearly understood about how the virus regulates its own expression and deregulates cellular transcription to efficiently replicate and evade immune responses. To understand the mechanisms of KSHV persistence, concentrated on at the level of gene expression regulation and immune evasion, four laboratories in California join forces. The following four projects will be primarily addressed: 1) the mechanism of inhibition on type inhibiting interferon production by KSHV ORF36 (project leader: Ren Sun, UCLA); 2) the transcriptional regulatory role of ORF36 as the sole viral kinase of KSHV (project leader: Hsing-Jien Kung, UC Davis); 3) the mechanism underlying two KSHV-encoded modulators (ORFI0 and ORF45) of innate immune pathways (project leader, Don Ganem, UCSF); 4) development of develop a non-human primate model for the KSHV persistent infection of KSHV to determine the immune evasive role of ORFI, ORF36, K-bZIPPRF45 and K5K3 during viral infection in vivo (project leader: Jae Jung, Harvard/USC).