KSHV alteration of cellular metabolism

卡波西肉瘤（Kaposi's Sarcoma，KS）是世界范围内艾滋病患者最常见的肿瘤， 在非洲部分地区发现了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），一种γ- 疱疹病毒KSHV在肿瘤中超过95%的梭形细胞中潜伏， 支持裂解复制的梭形细胞。培养物中内皮细胞的感染导致类似百分比的 潜伏性和溶解性感染导致我们使用培养的内皮细胞感染作为感染模型。我们有 表明KSHV感染后显著改变内皮细胞代谢，包括诱导内皮细胞凋亡， 糖酵解、脂肪胺解和脂肪酸合成。有趣的是，所有这些代谢途径也 在来自多种癌症的肿瘤细胞中诱导，并且是癌细胞存活所需的。抑制 这些途径在潜伏感染的细胞中诱导细胞死亡，但在模拟感染的细胞中不诱导细胞死亡，这表明这是一种潜在的感染途径。 潜在的治疗靶点。这些通路以线粒体为中心。初步 我们发现线粒体翻译对于潜伏感染的细胞增殖和存活是必要的， 细胞在这个建议中，我们将确定线粒体在KSHV潜伏期中的作用，以及KSHV如何直接 改变线粒体，导致线粒体功能改变。我们还将研究如何KSHV改变 改变了潜伏感染细胞中的其他代谢途径。这些研究将揭示 KSHV潜伏感染内皮细胞如何需要改变细胞代谢以通过以下途径存活： 确定KSHV如何改变细胞应激和线粒体以及相关的病毒机制。 本提案中检查的一些线粒体途径是FDA批准的治疗靶点 药物，并有可能用于靶向KSHV潜伏感染，最终KS肿瘤。 !

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. !