C-X-C Chemokines and Kaposi's Sarcoma

描述：(申请人提供)趋化因子是一种小的、具有化学吸引力的物质 属于细胞因子家族的分子。这两个主要群体 趋化因子是C-X-C和C-C趋化因子及其受体 C-X-C和C-C趋化因子已被证明是HIV-1的重要辅助受体 和HIV-2病毒。我们现在已经证明了HIV-1感染单核细胞 导致大量增加的C-X-C 趋化因子白介素8(IL-8)和生长相关癌基因a(GRO-a)。我们有 也表明Gro-a产量的增加是通过相互作用调节的 病毒gpl2O与CXCR4的结合和对IL-8的刺激是由gp120和 病毒反式激活蛋白Tat。IL-8和Gro-a都能刺激HIV-1 在单核细胞和T细胞中复制，从而完成自分泌循环 这将有利于艾滋病毒-L的复制。 Gro-Cx和IL-8是血管生成趋化因子，最近也被证明 通过Kaposi肉瘤疱疹病毒(KSHV)编码的刺激信号 G蛋白偶联受体。我们的小组现在已经证明了Gro-a和IL-8 是由感染KSHV的人内皮细胞产生的，是主要的介体 在体外和小鼠模型中的血管生成的研究。因此，我们的假设是 提示内皮细胞感染KSHV，而邻近细胞感染HIV-1 单核细胞，导致C-X-C水平显著升高 趋化因子Gro-a和IL-8促进血管生成和KS的发生发展。 有鉴于此，我们现在建议进一步描述IL-8的作用 和Gro-a在KSHV的复制、转化和血管生成中的作用 KSHV感染内皮细胞的潜能。此外，使用量化 图像的单细胞分析，我们将检查是否水平的变化 IL-8和/或Gro-a表达与KSHV复制和/或 KS患者皮损的形态特征。此外，我们将调查 阻断这些趋化因子或其受体是否会影响KSHV 复制和/或干扰血管生成反应或内皮细胞 转型。因此，这项工作有可能将KSHV、增长因素、 和HIV/TAT在KS发病中的作用，并为KS的治疗提供新的途径 治疗这种复杂的肿瘤。

DESCRIPTION: (provided by applicant) The chemokines are small, chemo-attractant molecules which are a part of the cytokine family. The two major groups of chemokines are the C-X-C and C-C chemokines and the receptors for specific C-X-C and C-C chemokines have been shown to be important coreceptors for HIV-1 and HIV-2. We have now demonstrated that infection of monocytic cells by HIV-1 leads to the elaboration of substantially increased amounts of the C-X-C chemokines interleukin-8 (IL-8) and growth-related oncogene a (GRO-a). We have also shown that the increased production of GRO-a is mediated by interaction of the viral gpl2O with CXCR4 and stimulation of LL-8 is mediated by gp120 and the viral transactivating protein Tat. Both IL-8 and GRO-a then stimulate HIV-1 replication in monocytic cells and T cells, thus completing an autocrine loop which would favor HIV-l replication. GRO-cx and IL-8 are angiogenic chemokines, which have also recently been shown to stimulate signaling through the Kaposi's Sarcoma Herpesvirus (KSHV)-encoded G protein coupled receptor. Our group has now demonstrated that GRO-a and IL-8 are produced by KSHV-infected human endothelial cells, and are major mediators of angiogenesis in vitro and in a mouse model. Therefore, our hypothesis is that KSHV infection of endothelial cells, and HIV-1 infection of adjacent monocytic cells, leads to substantial increases in the level of the C-X-C chemokines GRO-a and IL-8, promoting angiogenesis and the development of KS. In view of the above, we now propose to further characterize the role of IL-8 and GRO-a in the replication of KSHV and in the transformation and angiogenic potential of KSHV-infected endothelial cells. In addition, using quantitative image single cell analysis, we will examine whether changes in the levels of IL-8 and/or GRO-a expression are associated with KSHV replication and/or morphologic patterns in KS lesions from patients. Further, we will investigate whether blocking these chemokines or their receptors will affect KSHV replication and/or interfere with the angiogenic response or endothelial cell transformation. This work thus has the potential to link KSHV, growth factors, and HIV/Tat in the pathogenesis of KS, and to suggest new avenues for the treatment of this complex neoplasm.