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)，也被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HHV-8感染KS的发病机制尚不清楚，但最近的证据表明，细胞在裂解期病毒复制过程中表达旁分泌因子是重要的。HHV-8趋化因子受体同源物ORF74是一种裂解期基因产物，在没有附加配体的情况下激活包括NFkB、NF-AT和AP-1在内的多个信号通路，并诱导促炎细胞因子和细胞黏附分子的表达。我们推测，NFkappaB、NF-AT和AP-1的激活依赖于PI-3激酶-Akt通路的信号传递，并导致促炎因子的表达，这些因子的长期异常表达最终导致肿瘤的形成。与HIV-1混合感染是KS发生的一个极其强烈的风险因素。我们推测HIV-1的Tat蛋白与ORF74通过PI-3激酶-Akt途径激活NFkappaB、NF-AT和AP-1，从而增强ORF74介导的肿瘤发生。中心假设是Akt是这些ORF74依赖过程的关键调节因子。为了验证这些假说，我们将表征ORF74激活NFKappaB、NF-AT和AP-1以及通过PI-3 Kinase-Akt诱导促炎和抗凋亡因子，并将确定ORF74介导的小鼠肿瘤形成是否依赖于通过PI-3 Kinase-Akt和GSK-3激活NFkappaB、NFAT和AP-1。我们还将确定TAT是否通过PI-3激酶-Akt和GSK-3增强ORF74对NFkappaB、NF-AT和AP-1的激活，并增强ORF74在小鼠中的肿瘤形成。这些研究将对ORF74在KS发病机制中的作用提供有价值的见解，并揭示HIV-1与HHV-8在导致KS中协同作用的机制。

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.