Immune Evasion by Gamma 2 Herpesviruses
Gamma 2 疱疹病毒的免疫逃避
基本信息
- 批准号:7756389
- 负责人:
- 金额:$ 32.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-08-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:ALCAM geneAcquired Immunodeficiency SyndromeActivated-Leukocyte Cell Adhesion MoleculeAddressAdhesionsAdhesivesAntigensAntiviral AgentsB-LymphocytesBone MarrowC-terminalCell AdhesionCell Adhesion MoleculesCell membraneCell physiologyCellsCellular MembraneCytotoxic T-LymphocytesDataDefense MechanismsDevelopmentDown-RegulationEndothelial CellsF-ActinFamilyFamily memberFilovirusFundingGasesGoalsHIV-1Hela CellsHerpesviridaeHomologous GeneHumanHuman Herpesvirus 8ImmuneImmune responseImmune systemImmunocompromised HostIndividualInfectionInfiltrationInflammationInflammatoryIntegral Membrane ProteinInterferonsKaposi SarcomaLatent VirusLesionLeukocytesLysineMaintenanceMalignant NeoplasmsMediatingMembraneMembrane MicrodomainsMolecularN-terminalNamesNatural Killer CellsOpen Reading FramesPatientsPlayProcessProliferatingProtein FamilyProteinsProteomeProteomicsPublishingRecruitment ActivityResistanceRetroviridaeRoleStructureSubstrate SpecificityTransmembrane DomainUbiquitinUbiquitin-Conjugating EnzymesUbiquitinationViralViral PathogenesisVirionVirusWorkangiogenesisbeta catenincadherin 5gamma-2 herpesvirushuman PHEMX proteinimmune clearancein vitro Modelinsightmonocyteneoplastic cellneutrophilparticleprotein Btumorubiquitin ligasevpu Protein
项目摘要
Kaposi's sarcoma, the most prevalent malignancy in AIDS patients, is characterized by proliferating spindle
cells of endothelial cell (EC) origin, infiltration by inflammatory cells and the presence of the KS herpesvirus
(KSHV) in lesions. The ultimate goal of our work is to understand how viral immune evasion mechanisms
contribute to viral pathogenesis and the d evelopment of KS. We focus on the function of two closely related
open reading frames, K3 and K5. These proteins, aka MIR1 and MIR2, are viral homologs of the cellular
membrane-associated RI NG-CH (MARCH) protein family comprising transmembrane ubiquitin Ii gases that
recruit cellular ubiquitin-conjugating enzymes for degradation of transmembrane proteins. While K3
predominantly targets host proteins invovled in alerting the cellular immune system, our work revealed that K5
substrates include EC-specific adhesion molecules (ALCAM, CD3IIPECAM, VE-Cadherin, alpha and beta-
Catenin) and the interferon-induced antiviral protein B ST2/Tetherin. We therefore hypothesize that K5
modulates innate immune defense as well as angioproliferative and inflammatory processes during KS
development. Specifically, we will address two major questions: 1) What are the consequences of K5
expression for the function of KSHV-infected ECs and their interaction with innate immune cells? Using ECbased
in vitro models of KS we will examine the modulation of EC/EC and EC/leukocyte adhesion by KSHV. 2)
Why and how does KSHV eliminate BST2/Tetherin? Preliminary data show that K5 ubiquitinates and degrades
BST2/Tetherin which tethers enveloped viral particles to host cell membranes. We will examine the hypothesis
that K5 counteracts the inhibition of KSHV egress by BST2. Upon completion of these studies we will have a
better understanding of viral modulation of host processes that are expected to be central to the establishment
and maintenance of longterm infection in healthy individuals and KS development in the immunocompromised.
卡波西肉瘤是艾滋病患者中最常见的恶性肿瘤,其特点是纺锤体增殖
内皮细胞 (EC) 来源的细胞、炎症细胞浸润以及 KS 疱疹病毒的存在
(KSHV)在病变中。我们工作的最终目标是了解病毒免疫逃避机制
有助于病毒发病机制和 KS 的发展。我们重点关注两个密切相关的功能
开放阅读框 K3 和 K5。这些蛋白质,又名 MIR1 和 MIR2,是细胞的病毒同源物
膜相关 RI NG-CH (MARCH) 蛋白家族,包含跨膜泛素 Ii 气体,
招募细胞泛素结合酶来降解跨膜蛋白。而K3
主要针对参与提醒细胞免疫系统的宿主蛋白,我们的工作表明,K5
底物包括 EC 特异性粘附分子(ALCAM、CD3IIPECAM、VE-钙粘蛋白、α 和 β-
Catenin)和干扰素诱导的抗病毒蛋白 B ST2/Tetherin。因此我们假设 K5
在 KS 期间调节先天免疫防御以及血管增殖和炎症过程
发展。具体来说,我们将解决两个主要问题:1)K5的后果是什么
KSHV 感染的 EC 功能的表达及其与先天免疫细胞的相互作用?使用基于 EC 的
在 KS 体外模型中,我们将检查 KSHV 对 EC/EC 和 EC/白细胞粘附的调节。 2)
KSHV 为何以及如何消除 BST2/Tetherin?初步数据显示K5泛素化并降解
BST2/Tetherin 将包膜病毒颗粒束缚到宿主细胞膜上。我们将检验假设
K5 抵消了 BST2 对 KSHV 排出的抑制。完成这些研究后,我们将获得
更好地了解病毒对宿主过程的调节,预计这对于建立病毒至关重要
健康个体中长期感染的维持以及免疫功能低下者中 KS 的发展。
项目成果
期刊论文数量(0)
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Klaus J Fruh其他文献
Klaus J Fruh的其他文献
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