KSHV alteration of cellular metabolism

 描述(由申请人提供)： 机会性感染是发展中国家艾滋病患者发病和死亡的主要原因，艾滋病患者容易患上由机会性感染引起的多种癌症。卡波西氏肉瘤(KS)是艾滋病患者中最常见的肿瘤，也是非洲部分地区最常见的肿瘤。KS的病原体是卡波西肉瘤相关疱疹病毒(KSHV或HHV-8)。KSHV总是在主要的KS肿瘤细胞中发现，梭形细胞是一种内皮源性细胞，主要处于潜伏状态。目前还没有针对疱疹病毒潜伏感染的药物。因此，一个重要的治疗方法是描绘和靶向KSHV潜伏期所需的宿主内皮细胞过程。最近的研究表明，细胞代谢的病理变化可能是肿瘤发生的驱动因素，而不仅仅是对肿瘤环境的适应。虽然有几项研究检测了病毒裂解感染期间细胞代谢的变化，但我们是第一个检测潜伏感染期间细胞代谢变化的研究。我们证明了内皮细胞潜伏感染KSHV会导致葡萄糖碳利用的改变，特别是引起有氧糖酵解。重要的是，我们发现 KSHV对有氧糖酵解的诱导对于潜伏感染细胞的生存至关重要。我们的初步数据表明，潜伏的KSHV感染也会诱导谷氨酰胺摄取，并需要谷氨酰胺来维持潜伏感染细胞的生存。因此，改变葡萄糖和谷氨酰胺的利用，对维持KSHV潜伏期至关重要。在这项建议中，我们将研究如何在潜伏感染KSHV的内皮细胞中特异性地利用葡萄糖和谷氨酰胺，KSHV是KS肿瘤的相关细胞类型。在第一个目标中，我们将分析潜伏感染期间的葡萄糖代谢，以进一步确定葡萄糖碳水化合物是如何代谢的，以及为什么潜伏感染的生存需要这些变化。我们还将研究诱导葡萄糖利用改变的细胞和病毒机制。在第二个目标中，我们将分析谷氨酰胺摄取增加的细胞和病毒机制，并确定谷氨酰胺在潜伏感染期间是如何代谢的。我们的数据表明，KSHV引起的细胞代谢的病理变化可能为潜伏感染的细胞提供新的治疗靶点，并最终为艾滋病患者的KS肿瘤提供治疗靶点。

 DESCRIPTION (provided by applicant): Opportunistic infections are a major cause of morbidity and mortality of AIDS patients in developing countries and AIDS patients are susceptible to a number of cancers caused by opportunistic infections. Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients and is the most commonly reported tumor overall in parts of Africa. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8). KSHV is invariably found in the main KS tumor cell, the spindle cell, a cell of endothelial origin and is predominantly found in th latent state. There are no drugs to target latent infection of herpesviruses. Therefore, an important therapeutic approach is to delineate and target host endothelial cell processes required for KSHV latency. Recent studies have shown that pathologic changes in cell metabolism can be a driver of oncogenesis rather than simply an adaptation to the tumor environment. While a few studies have examined alterations of cellular metabolism during lytic infection of viruses, we were the first to examine changes in cellular metabolism during latent infection. We demonstrated that latent KSHV infection of endothelial cells leads to an alteration in glucose carbon utilization, specifically inducing aerobic glycolysis. Importantly, we found that KSHV induction of aerobic glycolysis is essential for the survival of latently infected cells. Our preliminary data for this proposal show that latent KSHV infection also induces glutamine uptake and requires glutamine for the survival of latently infected cells. Therefore, altered utilization f both glucose and glutamine, are critical for the maintenance of KSHV latency. In this proposal, we will examine how glucose and glutamine are utilized specifically in endothelial cells latently infected with KSHV, the relevant cell type for KS tumors. In the first aim we will analyze glucose metabolism during latent infection to further identify how glucose carbons are metabolized and why these alterations are needed for the survival of latent infection. We will also examine the cellular and viral mechanisms for induction of altered glucose utilization. In the second aim we will analyze the cellular and viral mechanism of increased glutamine uptake and determine how glutamine is metabolized during latent infection. Our data indicate that pathologic changes in cellular metabolism induced by KSHV could provide novel therapeutic targets for latently infected cells and would ultimately provide therapeutic targets for KS tumors in AIDS patients.