Immune Evasion by Gamma 2 Herpesviruses

Gamma 2 疱疹病毒的免疫逃避

• 批准号: 7756389
• 负责人: Klaus J Fruh
• 金额: $ 32.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7756389
• 关键词: ALCAM gene; Acquired Immunodeficiency Syndrome; Activated-Leukocyte Cell Adhesion Molecule; Address; Adhesions; Adhesives; Antigens; Antiviral Agents; B-Lymphocytes; Bone Marrow; C-terminal; Cell Adhesion; Cell Adhesion Molecules; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cytotoxic T-Lymphocytes; Data; Defense Mechanisms; Development; Down-Regulation; Endothelial Cells; F-Actin; Family; Family member; Filovirus; Funding; Gases; Goals; HIV-1; Hela Cells; Herpesviridae; Homologous Gene; Human; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunocompromised Host; Individual; Infection; Infiltration; Inflammation; Inflammatory; Integral Membrane Protein; Interferons; Kaposi Sarcoma; Latent Virus; Lesion; Leukocytes; Lysine; Maintenance; Malignant Neoplasms; Mediating; Membrane; Membrane Microdomains; Molecular; N-terminal; Names; Natural Killer Cells; Open Reading Frames; Patients; Play; Process; Proliferating; Protein Family; Proteins; Proteome; Proteomics; Publishing; Recruitment Activity; Resistance; Retroviridae; Role; Structure; Substrate Specificity; Transmembrane Domain; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; Viral; Viral Pathogenesis; Virion; Virus; Work; angiogenesis; beta catenin; cadherin 5; gamma-2 herpesvirus; human PHEMX protein; immune clearance; in vitro Model; insight; monocyte; neoplastic cell; neutrophil; particle; protein B; tumor; ubiquitin ligase; vpu Protein

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.

Kaposi的肉瘤是艾滋病患者中最普遍的恶性肿瘤，其特征是纺锤体增殖 内皮细胞（EC）起源的细胞，炎症细胞浸润和KS疱疹病毒的存在 （KSHV）病变。我们工作的最终目标是了解病毒免疫逃避机制如何 有助于病毒发病机理和KS的de摄取。我们专注于两个密切相关的功能 打开阅读框架，K3和K5。这些蛋白（又称miR1和miR2）是细胞的病毒同源物 膜相关的RI NG-CH（3月）蛋白家族，包括跨膜泛素II气体 募集细胞泛素结合酶以降解跨膜蛋白。而K3 我们的工作主要靶向宿主蛋白，以提醒细胞免疫系统，我们的工作表明K5 底物包括EC特异性粘附分子（Alcam，CD3IIPECAM，VE-Cadherin，Alpha和beta-- Catenin）和干扰素诱导的抗病毒药蛋白B ST2/Tetherin。因此，我们假设K5 调节KS的先天免疫防御以及血管增生性和炎症过程 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EC的功能及其与先天免疫细胞的相互作用的表达？使用污染 KS的体外模型我们将通过KSHV检查EC/EC/EC/白细胞粘附的调节。 2） KSHV为什么以及如何消除BST2/Tetherin？初步数据显示K5泛素化和降解 BST2/TETHERIN，将病毒颗粒包裹在宿主细胞膜上。我们将检查假设 K5抵消了BST2对KSHV出口的抑制。完成这些研究后，我们将有一个 更好地理解对宿主过程的病毒调制，这些过程对建立至关重要 并维持健康个体的长期感染和免疫功能低下的KS发育。