KSHV Latent Infection Replication

KSHV 潜伏感染复制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的卡波西肉瘤 (KS) 疱疹病毒 (KSHV) 是 KS（原发性渗出性淋巴瘤）的病原体 (PEL) 和多中心卡斯尔曼病 (MCD) 这些肿瘤最常见于患有此病的个体。艾滋病或其他免疫功能低下的疾病目前没有针对这些疾病的具体疗法。 KS 是主要的艾滋病恶性肿瘤，在撒哈拉以南非洲地区流行。口腔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，无法抑制这种表达。导致抑制性 H2AK119ub 和 H3K27me3 修饰随后累积到与经典的相反，沉默裂解基因启动子首先产生，然后是 H3K27me3。其中 H3K27me3 标记先于 H2AK119ub 的模型。潜伏性是 KSHV 和伽玛疱疹病毒感染的标志，它会潜伏感染细胞，包括细胞。肿瘤细胞和病毒基因组以环状、染色体外、多拷贝、附加体的形式存在。增殖细胞中，病毒附加体必须复制，随后分离到子肿瘤细胞。生存能力取决于潜伏的 KSHV 感染。潜伏相关核抗原（LANA）是表达于细胞中的有限数量的病毒基因之一。 LANA 负责 KSHV 附加体的维持，对于病毒附加体来说是必要且充分的。在没有其他病毒基因的情况下的持久性除了附加体持久性之外，LANA 也发挥着重要作用。 LANA 参与转录调控和生长控制。我们发现 LANA 与 DNA 损伤反应 (DDR) 的一个组成部分相互作用，并且 DDR 在感染后沉默病毒基因组，从而抑制裂解复制并允许潜伏期这项工作将采用严谨、细致、深入的方法来研究其机制基础。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，我们将研究关键 DDR 的动态和沉积位点。 KSHV 基因组的因素和 LANA 在这些事件中的作用也将被研究。 DDR 建立 KSHV 抑制性表观基因组感染后 KSHV 基因组沉默。病毒潜伏期的建立至关重要，因此这项工作为病毒潜伏期的建立提供了新颖而重要的见解 KSHV 生物学的基本组成部分。