KSHV alteration of cellular metabolism

卡波西氏肉瘤(KS)是全世界艾滋病患者最常见的肿瘤，也是最常见的 据报道，非洲部分地区出现肿瘤。主要的肿瘤细胞是梭形细胞，一种内皮来源的细胞。 KS的病原体是卡波西肉瘤相关疱疹病毒(KSHV或HHV-8)，是一种伽玛病毒 疱疹病毒。KSHV在肿瘤中95%以上的梭形细胞中潜伏，低比例的 支持裂解复制的梭形细胞。培养中内皮细胞的感染导致相似百分比的 潜伏感染和裂解感染导致我们使用培养的内皮细胞感染作为感染的模型。我们有 证明KSHV在感染时显著改变内皮细胞的代谢，包括诱导 糖酵解、谷氨酰胺分解和脂肪酸合成。有趣的是，所有这些代谢途径也是 在各种癌症的肿瘤细胞中诱导，是癌细胞生存所必需的。抑制 这些途径在潜伏感染细胞中诱导细胞死亡，但不诱导模拟感染细胞死亡，这表明这是一种 潜在的干预治疗靶点。这些途径以线粒体为中心。在预赛中 我们发现线粒体的翻译对于潜伏感染的人的增殖和生存是必要的 细胞。在这个方案中，我们将确定线粒体在KSHV潜伏期中的作用以及KSHV是如何直接 改变线粒体，导致线粒体功能改变。我们还将研究KSHV如何改变 线粒体的改变改变了潜伏感染细胞中的其他代谢途径。这些研究将有助于 KSHV潜伏感染内皮细胞如何通过改变细胞代谢才能存活 确定KSHV如何改变细胞应激和线粒体以及涉及的病毒机制。 这项提案中研究的许多线粒体途径都是FDA批准的治疗靶点 药物，并可能被用于靶向KSHV潜伏感染，最终靶向KS肿瘤。 好了！

Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients worldwide and is the most commonly reported tumor in parts of Africa. The predominant tumor cell is the spindle cell, a cell of endothelial origin. The etiologic agent of KS is the Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8), a gamma herpesvirus. KSHV is latent in greater than 95% of the spindle cells in the tumor, with a low percentage of spindle cells supporting lytic replication. Infection of endothelial cells in culture leads to similar percentages of latent and lytic infection leading us to use cultured endothelial cell infection as a model of infection. We have demonstrated that KSHV dramatically alters endothelial cell metabolism upon infection including induction of glycolysis, glutaminolysis and fatty acid synthesis. Interestingly, all of these metabolic pathways are also induced in tumor cells from a variety of cancers and are required for the survival of cancer cells. Inhibition of these pathways induces cell death in latently infected cells but not mock infected cells indicating that this is a potential therapeutic target for intervention. These pathways center around the mitochondria. In preliminary data we found that mitochondrial translation is necessary for proliferation and survival of latently infected cells. In this proposal we will determine the role of the mitochondria in KSHV latency and how KSHV directly alters the mitochondria leading to altered mitochondrial function. We will also examine how KSHV alteration of mitochondria alters other metabolic pathways in the latently infected cells. These studies will shed light on how KSHV latent infection of endothelial cells requires alterations in cellular metabolism for survival through determination of how KSHV alters cellular stress and mitochondria as well as the viral mechanisms involved. A number of the mitochondrial pathway examined in this proposal are therapeutic targets with FDA approved drugs and could potentially be used to target KSHV latent infection and ultimately KS tumors. !