KSHV Latent Infection Replication

KSHV 潜伏感染复制

• 批准号: 10271003
• 负责人: Kenneth M Kaye
• 金额: $ 63.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271003
• 关键词: Acquired Immunodeficiency Syndrome; Africa South of the Sahara; Antiviral Response; Biochemical; Biology; Blood group antigen S; Cell Nucleus; Cell Survival; Cell division; Cells; ChIP-seq; Chromatin; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA amplification; DNA damage checkpoint; Daughter; Deposition; Development; Disease; Epidemic; Epigenetic Process; Episome; Etiology; Event; Failure; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome; Growth; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immunocompromised Host; Individual; Infection; Kaposi Sarcoma; Knockout Mice; Link; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Mediator of activation protein; Modeling; Modification; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Nature; Oral cavity; Organ; Polycomb; Process; Proliferating; Proteins; Quality Control; Role; Saliva; Site; Stimulus; Transcriptional Activation; Transcriptional Regulation; Viral; Viral Genes; Viral Genome; Virus; Virus Latency; Visceral; Work; epigenome; experimental study; gammaherpesvirus; in vivo; insight; latency-associated nuclear antigen; latent infection; lytic gene expression; lytic replication; neoplastic cell; novel; prevent; primary effusion lymphoma; promoter; recruit; repaired; response; transmission process; tumor; ubiquitin-protein ligase

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.

摘要 卡波西肉瘤（KS）疱疹病毒（KSHV）是原发性渗出性淋巴瘤KS的病原体 (PEL)和多中心Castleman病（MCD）。这些肿瘤最常发生在患有 艾滋病或其他免疫系统疾病。目前，对这些疾病没有具体的治疗方法。 KS是主要的艾滋病恶性肿瘤，并且在整个撒哈拉以南非洲流行。KS通常涉及 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 导致裂解性复制。抑制性H2 AK 119 ub和H3 K27 me 3修饰随后累积， 沉默裂解基因启动子。H2 AK 119 ub最初累积，随后是H3 K27 me 3，与经典的 其中H3 K27 me 3标记先于H2 AK 119 ub。 潜伏期是KSHV和γ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作为环状的、染色体外的、多拷贝的附加体持续存在。坚持 在增殖细胞中，病毒游离体必须复制，随后分离成子核。肿瘤细胞 生存力取决于潜伏的KSHV感染。 潜伏相关核抗原（拉娜）是在大肠杆菌中表达的有限数量的病毒基因之一。 延迟。拉娜负责KSHV附加体的维持，是病毒附加体维持的必要和充分条件 在没有其他病毒基因的情况下持续存在。除了附加体持久性，拉娜发挥重要的 在转录调控和生长控制中的作用。拉娜参与沉默病毒基因组。 我们已经发现拉娜与DNA损伤反应（DDR）的一个组分相互作用， 感染后，DDR使病毒基因组沉默，从而抑制裂解复制并允许潜伏期 建立。这项工作将使用严格的，详细的，深入的方法来调查的机制基础 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， 和抑制裂解性复制。我们将调查主要复员方案的动态和沉积地点， KSHV基因组上的因子和拉娜在这些事件中的作用。实验还将调查的作用， 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 核心的病毒潜伏期的建立，因此这项工作提供了新的和重要的见解， KSHV生物学的基本组成部分。