Interactions of KSHV and endothelial cells

描述（由申请人提供）： 卡波西肉瘤（KS）是艾滋病患者在这个国家广泛使用高效抗逆转录病毒治疗之前最常见的肿瘤。KS是目前非洲地区最常见的肿瘤。卡波济肉瘤相关疱疹病毒（Kaposi's Sarcoma-associated herpesvirus，KSHV）是卡波济肉瘤的重要病原体。在KS中，在梭形细胞中发现KSHV，梭形细胞是KS的肿瘤细胞，是内皮来源的细胞。KSHV也与原发性渗出性淋巴瘤（PEL）有关，这是一种B细胞淋巴增生性疾病。已经建立了PEL细胞系，并用于KSHV的许多研究。然而，KS是一种基于内皮细胞的肿瘤，因此研究内皮细胞中的KSHV也很重要。疱疹病毒的特征都在于具有潜伏感染和裂解感染，潜伏感染中病毒在宿主的生命中维持但不产生感染性颗粒，裂解感染中病毒复制并裂解宿主细胞。有趣的是，KS显然需要裂解和潜伏期感染的形成和维护。由于裂解感染的细胞正在死亡，因此必须产生作用于潜伏感染细胞的旁分泌因子。我们建议通过研究裂解基因在潜伏感染的内皮细胞中的作用来表征裂解基因表达在KS维持中的功能。我们已经建立了一个研究内皮细胞中KSHV的易处理系统，我们将研究KSHV基因在我们的内皮细胞系统中的表达和功能。我们将创建和纯化重组KSHV分离株删除突出的裂解基因参与信号转导。随后的分析将描述这些基因在裂解和潜伏感染中的作用。我们将分析裂解感染过程中的生长和信号传导能力，并分析这些裂解基因如何改变潜伏感染细胞中的宿主转录。

DESCRIPTION (provided by applicant): Kaposi's Sarcoma (KS) was the most common tumor in Aids patients in this country before the wide spread use of highly active antiretroviral therapy. KS is currently the most commonly reported tumor in regions of Africa. Kaposi's Sarcoma-associated herpesvirus (KSHV, formally known as human herpesvirus 8, HHV-8) is an essential etiologic agent for KS. In KS, KSHV is found in the spindle cell, a cell of endothelial origin that is the tumor cell of KS. KSHV is also associated with primary effusion lymphoma (PEL), a B-cell lymphoproliferative disorder. PEL cell lines have been created and are used for many studies of KSHV. However, KS is an endothelial cell based neoplasm and thus it is important to study KSHV in endothelial cells as well. Herpesviruses are all characterized by having latent infection, where the virus is maintained for the life of the host but does not produce infectious particles, and lytic infection, where the virus replicates and lyses the host cell. Interestingly, KS apparently requires both lytic and latent phase infection for formation and maintenance. Since the lytically infected cell is dying, there must be paracrine factors produced that act on latently infected cells. We propose to characterize the function of lytic gene expression in maintenance of KS by studying the role of lytic genes in latently infected endothelial cells. We have created a tractable system for studying KSHV in endothelial cells and we will study KSHV gene expression and function in our endothelial cell system. We will create and purify recombinant KSHV isolates deleted in prominent lytic genes involved in signal transduction. Subsequent analysis will characterize the role of these genes in both lytic and latent infection. We will analyze growth and signaling capabilities during lytic infection and we will analyze how these lytic genes alter host transcription in latently infected cells.