Immune Evasion and Protein Trafficking Piracy by KSHV

KSHV 的免疫逃避和蛋白质贩运盗版行为

• 批准号: 6791184
• 负责人: ROBERT E MEANS
• 金额: $ 0.55万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791184
• 关键词: Callithricidae; Herpesvirus saimiri; MHC class I antigen; artificial chromosomes; cell adhesion molecules; confocal scanning microscopy; cytotoxic T lymphocyte; endocytosis; human herpesvirus 8; immunoprecipitation; immunoregulation; intracellular transport; latent virus infection; natural killer cells; point mutation; protein localization; protein protein interaction; protein structure function; protein transport; recombinant virus; virus infection mechanism; virus receptors; yeast two hybrid system

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is the most recently described oncogenic, human herpesvirus. It is classified as a gamma-herpesvirus based on genome co-linearity and homology with several other members of this sub-group including Herpesvirus saimiri and Rhesus rhadinovirus. First identified through an association with the leading form of cancer striking HIV-infected individuals, it is now recognized that it is also the etiological agent of one of the leading causes of cancer deaths in Africa. A hallmark of the herpesviruses are their ability to persist within the host despite the presence of strong antiviral responses. In order to accomplish this feat, these viruses have evolved a number of stratagies to harness, alter and avoid the immune responses. One common stratagy is the removal of MHC class I from the surface of infected cells. Without MHC class I molecules on their surface, cells are unable to signal their infected status to immune effector cells and trigger strong, specific antiviral responses. KSHV accomplishes the removal of MHC class I from infected cells by the expression of two related gene products, K3 and K5. Additionally, the K5 protein removes at least two other molecules from the surface of cells, B7-2 and ICAM, which are critical in the regulation of components of both the innate and adaptive immune responses. Thus, KSHV has developed a single stratagy theoretically capable of pan-immune escape. A better understanding of the molecular mechanisms by which K3 and K5 control the host immune response is critical for the design of anti-viral theraputics against not only KSHV, but other herpesviruses. The goals of this project are to: (1) Utilize biochemical and microscopic techniques to define specific cellular partners of K3 and K5, which have been co-opted by KSHV to downregulate the various cell surface targets, and (2) delineate the importance of K3 and K5 to in vivo viral persistence and pathogenicity through the use of a non-human primate herpesvirus model and specific herpesvirus saimiri recombinants. These studies will facilitate a better understanding, not only of the importance of this immune evasion strategy employed by KSHV, but also of the relative importance of innate and adaptive anti-viral immune responses in controlling herpesvirus persistence. In addition, characterization of the K5-binding partners should provide insights into the cellular biology underlying protein trafficking within the cell.

描述（由申请人提供）：Kaposi与肉瘤相关的疱疹病毒（KSHV）是最近描述的致癌性人体疱疹病毒。 它被归类为基于基因组共线性和同源性的伽马病毒病毒，并与该子组的其他几个成员（包括疱疹病毒saimiri和Rhesus rhadinovirus）分类为同源性。 首先是通过与癌症感染的艾滋病毒感染者的主要形式相关的，现在已经认识到，它也是非洲癌症死亡的主要原因之一的病因学药。 尽管存在强烈的抗病毒药反应，但疱疹病毒的标志是它们在宿主内持续存在的能力。 为了实现这一壮举，这些病毒已经发展了许多层次，以利用，改变和避免免疫反应。 一种常见的层状是从感染细胞的表面去除MHC I类。 如果没有MHC的表面I类分子，细胞就无法向免疫效应细胞发出感染状态并触发强，特定的抗病毒药反应。 KSHV通过表达两个相关基因K3和K5的表达来实现从感染细胞中MHC I类去除。 另外，K5蛋白从细胞表面B7-2和ICAM表面除去至少两个其他分子，这对于调节先天和适应性免疫反应的成分至关重要。 因此，KSHV开发了一个理论上能够泛节逃脱的单个策略。 对K3和K5控制宿主免疫反应的分子机制的更好理解对于不仅针对KSHV，而且其他疱疹病毒的抗病毒疗法设计至关重要。 The goals of this project are to: (1) Utilize biochemical and microscopic techniques to define specific cellular partners of K3 and K5, which have been co-opted by KSHV to downregulate the various cell surface targets, and (2) delineate the importance of K3 and K5 to in vivo viral persistence and pathogenicity through the use of a non-human primate herpesvirus model and specific疱疹病毒Saimiri重组。 这些研究将促进更好的理解，不仅是KSHV采用的这种免疫逃避策略的重要性，而且对先天和适应性抗病毒免疫反应在控制疱疹病毒持久性中的相对重要性。 此外，K5结合伴侣的表征应提供对细胞内蛋白质运输的细胞生物学的见解。