KSHV Latent Infection Replication

摘要 卡波西肉瘤(KS)疱疹病毒(KSHV)是原发渗出性淋巴瘤KS的病原体 (PEL)和多中心Castleman病(MCD)。这些肿瘤最常发生在有 艾滋病或其他影响免疫的疾病。目前，还没有针对这些疾病的特效疗法。 KS是主要的艾滋病恶性肿瘤，流行于撒哈拉以南非洲。KS通常涉及 并可广泛传播至内脏器官。唾液是KSHV的传播媒介。 感染后，与转录激活相关的表观遗传修饰沉积在 KSHV基因组，导致广泛但短暂的病毒基因表达。未能抑制这种表达 导致裂解复制。抑制性的H2AK119ub和H3K27me3修饰随后累积到 沉默的裂解基因启动子。与经典的H3K27me3相比，H2 AK119 ub最初是累加的，随后是H3K27me3 H3K27me3标记在H2 AK119 ub之前的模型。 潜伏期是KSHV和伽马疱疹病毒感染的标志。KSHV潜伏感染细胞，包括 肿瘤细胞和病毒基因组以环状、染色体外、多拷贝、附着体的形式存在。坚持，坚持 在细胞增殖的情况下，病毒上皮体必须复制，然后分离到子核。肿瘤细胞 生存能力取决于潜伏的KSHV感染。 潜伏期相关核抗原(LANA)是在 延迟。LANA负责KSHV Episome的维护，对病毒Episome是必要和充分的 在没有其他病毒基因的情况下坚持下去。除了Episome持久力，LANA还发挥着重要的作用 在转录调控和生长控制中的作用。拉娜参与了病毒基因组的沉默。 我们已经发现LANA与DNA损伤反应(DDR)的一个组件相互作用，并且 DDR在感染后使病毒基因组沉默，从而抑制裂解复制并允许潜伏期 建制派。这项工作将使用严谨、详细、深入的方法来研究其机理基础 这些发现。实验将研究LANA-DDR相互作用及其在病毒基因组沉默中的作用， 和抑制裂解复制。我们将调查密钥DDR的沉积动力学和沉积地点 影响KSHV基因组的因素和LANA在这些事件中的作用。实验还将调查这两个基因的作用 DDR在建立KSHV抑制性表观基因组中的作用。感染后KSHV基因组的沉默是 对病毒潜伏期的建立至关重要，因此这项工作为我们提供了对 KSHV生物学的基本组成部分。

Abstract Kaposi's sarcoma (KS) herpesvirus (KSHV) is the etiologic agent of KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). These tumors occur most commonly in individuals with AIDS or other immunocompromising conditions. Currently, there are no specific therapies for these diseases. KS is the leading AIDS malignancy, and is epidemic throughout sub Saharan Africa. KS commonly involves the oral cavity and can widely disseminate to visceral organs. Saliva is the vehicle of transmission for KSHV. Following infection, epigenetic modifications associated with transcriptional activation are deposited on the KSHV genome, leading to widespread, but brief, viral gene expression. Failure to inhibit this expression leads to lytic replication. Repressive H2AK119ub and H3K27me3 modifications subsequently accumulate to silence lytic gene promoters. H2AK119ub accrues initially, followed by H3K27me3, in contrast to the classical model in which H3K27me3 marks precede H2AK119ub. Latency is the hallmark of KSHV and gammaherpesvirus infection. KSHV latently infects cells, including tumor cells, and viral genomes persist as circular, extrachromosomal, multi-copy, episomes. To persist in proliferating cells, viral episomes must replicate, and subsequently, segregate to daughter nuclei. Tumor cell viability is dependent on latent KSHV infection. The latency-associated nuclear antigen (LANA) is one of a limited number of virus genes expressed in latency. LANA is responsible for KSHV episome maintenance and is necessary and sufficient for virus episome persistence in the absence of other viral genes. In addition to episome persistence, LANA exerts important roles in transcriptional regulation and growth control. LANA is involved in silencing the viral genome. We have discovered LANA interacts with a component of the DNA damage response (DDR), and that the DDR silences the viral genome following infection, thereby inhibiting lytic replication and allowing latency establishment. This work will use rigorous, detailed, in depth approaches to investigate the mechanistic basis of these findings. Experiments will investigate the LANA-DDR interaction and its role in viral genome silencing, and suppression of lytic replication. We will investigate the dynamics and sites of deposition of key DDR factors on the KSHV genome and LANA’s role in these events. Experiments will also investigate the role of the DDR in establishing the KSHV repressive epigenome. The silencing of the KSHV genome following infection is central to the establishment of viral latency, and this work therefore provides novel and important insight into a fundamental component of KSHV biology.