KSHV Latent Infection Replication

KSHV 潜伏感染复制

基本信息

批准号：
10592298
负责人：
Kenneth M Kaye
金额：
$ 61.41万
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/10592298
关键词：
Acquired Immunodeficiency Syndrome Africa South of the Sahara Antiviral Response Biochemical Biology Cell Nucleus Cell Proliferation 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 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 segregation 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 Kaposi的肉瘤（KS）疱疹病毒（KSHV）是KS的病因，主要积液淋巴瘤（PEL）和多中心Castleman病（MCD）。这些肿瘤最常见于患有艾滋病或其他免疫促进性疾病。目前，这些疾病没有具体的疗法。 KS是领先的艾滋病恶性肿瘤，在整个撒哈拉以南非洲地区流行。 KS通常涉及口腔，可以广泛传播到内脏器官。唾液是KSHV传播的工具。感染后，将与转录激活相关的表观遗传修饰沉积在 KSHV基因组，导致宽度，但短暂的病毒基因表达。无法抑制这种表达导致裂解复制。抑制性H2AK119UB和H3K27ME3修改随后积累至静音裂解基因启动子。 H2AK119UB峰最初，其次是H3K27me3，与经典相反 H3K27me3标记H2AK119UB之前的模型。潜伏期是KSHV和Gammaherpesvirus感染的标志。 KSHV潜在感染的细胞，包括肿瘤细胞和病毒基因组持续存在为圆形，肿瘤外，多拷贝，偶发。坚持下去增殖的细胞，病毒发作必须复制，然后将其分离为子核。肿瘤细胞生存力取决于潜在的KSHV感染。与潜伏期相关的核抗原（LANA）是有限数量的病毒基因之一潜伏期。 Lana负责KSHV剧集维护，并且需要病毒发作的必要和足够在没有其他病毒基因的情况下持久性。除了情节持久性外，拉娜出口很重要在转录调控和生长控制中的作用。 Lana参与沉默病毒基因组。我们发现Lana与DNA损伤响应（DDR）的组成部分相互作用，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建立。这项工作将采用严格，详细的深入方法来研究机械基础这些发现。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。我们将研究关键DDR沉积的动力和位点 KSHV基因组和Lana在这些事件中的作用的因素。实验还将研究 DDR建立KSHV抑制表观基因组。感染后KSHV基因组的沉默是建立病毒潜伏期的核心，因此这项工作为一个新颖而重要 KSHV生物学的基本组成部分。