Role of MHV68 v-cyclin in virus egress

MHV68 v-cyclin 在病毒流出中的作用

基本信息

批准号：
8807186
负责人：
SAMUEL H SPECK
金额：
$ 23.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8807186
关键词：
1 year old 10 year old Actins Acute Adenoviruses Animal Model Apoptosis Attention B-Lymphocytes Binding Biochemical Biological Models CDK2 gene Cell Cycle Cell Cycle Progression Cell Death Induction Cell Line Cells Complex Cyclin A Cyclins Cytoskeletal Modeling Cytoskeleton DNA Viruses Defect Development Disease Environment Epithelial Cells Exhibits Foundations Future Genes Growth HIV Health Herpesviridae Herpesviridae Infections Homologous Gene Human Herpesvirus 4 Human Herpesvirus 8 In Vitro Individual Infection Life Cycle Stages Lung Lymphocyte Function Lymphoma Modeling Mus Necrosis Oncogenes Papillomavirus Phenotype Play Polyomavirus Property Proteins Rhadinovirus Role Saimiriine Herpesvirus 2 Structural Models Structure Technetium Tc 99m ciprofloxacin Transgenes Transgenic Mice Viral Virion Virus Virus Diseases Virus Replication Work base cell type gamma-2 herpesvirus gammaherpesvirus immunosuppressed in vivo insight macrophage mutant novel reactivation from latency tissue culture trafficking tumor viral cyclin

项目摘要

DESCRIPTION (provided by applicant): Gammaherpesviruses are associated with the development of lympho-proliferative disorders and lymphoma, particularly in immunosuppressed individuals. Indeed, half of the lymphomas that arise in HIV infected individuals are associated with either EBV or KSHV infection. Perturbation of host cell cycle is a common strategy employed by DNA viruses to achieve a cellular environment conducive to viral growth. Adenovirus, polyoma virus, papilloma virus, and many herpesviruses encode genes that directly alter the host cell cycle, or interact with host gene products to the same end. Rhadinoviruses (γ2-herpesviruses), such as Kaposi sarcoma-associated herpesvirus (KSHV), herpesvirus saimiri (HVS), and murine gammaherpesvirus-68 (MHV68), encode a homolog of mammalian D-type cyclins. We have previously shown that the MHV68 v-cyclin is required for: (i) efficient acute replication in the lungs of mice; and (ii) reactivation from latently infected macrophages and B cells. We have recently identified a tissue culture model that recapitulates the replication defect observed with v-cyclin null and v-cyclin CDK binding mutants in vivo. Further characterization of MHV68 replication in this tissue culture model has identified a profound defect in the egress of v-cyclin null and v-cyclin CDK binding mutants from infected cells. In this new R21 application, we propose to investigate the role that the MHV68 v-cyclin plays in virus egress/release from lung epithelial cells. The specific aims are as follows: Aim 1. Characterization of the v-cyclin null mutant MHV68 egress phenotype: 1.a Localization of virions in wt and v-cyclin mutant infected cells; 1.b Cellular localization of v-cyclin during virus infecton; 1.c Assess egress phenotype of a KSHV v-cyclin null mutant in HUVECs. Aim 2. Analysis of v-cyclin functions in the absence of MHV68 infection: 2.a Generate and characterize inducible v-cyclin expressing cell lines; 2.b Identify v-cyclin interacting partners.

描述（由申请人提供）：伽玛疱疹病毒与淋巴增殖性疾病和淋巴瘤的发生相关，特别是在免疫抑制个体中。事实上，HIV感染个体中出现的淋巴瘤中有一半与宿主的EBV或KSHV感染相关。细胞周期是 DNA 病毒用来实现有利于病毒生长的细胞环境的一种常见策略，它们编码基因。直接改变宿主细胞周期，或与宿主基因产物（γ2-疱疹病毒）相互作用，例如卡波西肉瘤相关疱疹病毒（KSHV）、赛米里疱疹病毒（HVS）和鼠伽马疱疹病毒-68（MHV68）。 )，编码哺乳动物 D 型细胞周期蛋白的同源物。我们之前已经证明，MHV68 v-细胞周期蛋白是以下功能所必需的：(i)小鼠肺部的有效急性复制；以及（ii）潜伏感染的巨噬细胞和 B 细胞的重新激活，我们最近发现了一种组织培养模型，该模型重现了体内 v-cyclin null 和 v-cyclin CDK 结合突变体观察到的复制缺陷。对该组织培养模型中 MHV68 复制的进一步表征发现，v-细胞周期蛋白无效和 v-细胞周期蛋白 CDK 结合突变体从受感染细胞中的输出存在严重缺陷。在新的 R21 应用中，我们建议研究 MHV68 v-cyclin 在病毒从肺上皮细胞流出/释放中所起的作用，具体目标如下：目的 1. v-cyclin 无效突变体 MHV68 流出表型的表征：1。 .a 病毒颗粒在 wt 和 v-cyclin 突变体感染细胞中的定位； 1.b 病毒感染期间 v-cyclin 的细胞定位；评估 HUVEC 中 KSHV v-细胞周期蛋白无效突变体的出口表型目标 2. 在没有 MHV68 感染的情况下分析 v-细胞周期蛋白功能： 2.a 生成并表征诱导型 v-细胞周期蛋白表达细胞系； 2.b 鉴定 v-细胞周期蛋白。细胞周期蛋白相互作用伙伴。