Pathogenic Mechanisms of HHV-8 ORF74

描述（由申请人提供）： 大量证据表明人类疱疹病毒8型（HHV-8），也称为卡波西肉瘤疱疹病毒（KSHV），是卡波西肉瘤（KS）的必要病原体。虽然KS发病机制的HHV-8还没有很好地理解，最近的证据表明，表达的旁分泌因子细胞裂解期病毒复制是很重要的。HHV-8趋化因子受体同源物ORF 74是一种裂解期基因产物，在没有添加配体的情况下激活几种信号传导途径，包括NF κ B、NF-AT和AP-1，并诱导促炎细胞因子和细胞粘附分子的表达。我们假设NF κ B、NF-AT和AP-1的激活依赖于通过PI-3激酶-Akt通路的信号传导，并导致促炎因子的表达，并且这些因子的慢性失调表达最终导致肿瘤形成。合并感染HIV-1是KS发展的一个非常强的风险因素。我们推测HIV-1的达特蛋白与ORF 74协同作用，通过PI-3激酶-Akt通路激活NF κ B、NF-AT和AP-1，并增强ORF 74介导的肿瘤发生。中心假设是Akt是这些ORF 74依赖性过程的关键介质。为了检验这些假设，我们将表征NF κ B、NF-AT和AP-1的ORF 74激活以及通过PI-3激酶-Akt诱导促炎和抗凋亡因子，并将确定小鼠模型中ORF 74介导的肿瘤发生是否依赖于通过PI-3激酶-Akt和GSK-3激活NF κ B、NFAT和AP-1。我们还将确定达特是否通过PI-3激酶-Akt和GSK-3增强NF κ B、NF-AT和AP-1的ORF 74活化，并增强小鼠中的ORF 74肿瘤发生。这些研究将为ORF 74对KS发病机制的贡献提供有价值的见解，并显示HIV-1与HHV-8合作导致KS的机制。

DESCRIPTION (provided by applicant): Considerable evidence implicates human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma herpesvirus (KSHV), as the necessary etiologic agent of Kaposi's sarcoma (KS). Although the mechanisms of KS pathogenesis by HHV-8 are not well understood, recent evidence suggests that expression of paracrine factors by cells undergoing lytic phase viral replication is important. The HHV-8 chemokine receptor homologue ORF74, a lytic phase gene product, activates several signaling pathways in the absence of added ligand, including NFkB, NF-AT and AP-1, and induces the expression of pro-inflammatory cytokines and cell adhesion molecules. We hypothesize that activation of NFkappaB, NF-AT and AP-1 depends on signaling via the PI-3 kinase-Akt pathway and causes the expression of pro-inflammatory factors, and that chronic dysregulated expression of these factors eventually results in tumor formation. Co-infection with HIV-1 is an extremely strong risk factor for KS development. We hypothesize that the Tat protein of HIV-1 synergizes with ORF74 in activating NFkappaB, NF-AT and AP-1 through the PI-3 kinase-Akt pathway and enhances ORF74-mediated tumorigenesis. The central hypothesis is that Akt is the key mediator of these ORF74-dependent processes. To test these hypotheses, we will characterize ORF74 activation of NFKappaB, NF-AT and AP-1 and induction of pro-inflammatory and anti-apoptotic factors via PI-3 kinase-Akt and will determine whether ORF74-mediated tumorigenesis in a mouse model depends on activation of NFkappaB, NFAT and AP-1 via PI-3 kinase-Akt and GSK-3. We will also determine whether Tat augments ORF74 activation of NFkappaB, NF-AT and AP-1 via PI-3 kinase-Akt and GSK-3 and enhances ORF74 tumorigenesis in mice. These studies should provide valuable insights on the contribution of ORF74 to KS pathogenesis and show a mechanism by which HIV-1 cooperates with HHV-8 in causing KS.