C-X-C Chemokines and Kaposi's Sarcoma

描述：（由申请人提供）趋化因子是小的化学引诱剂 这些分子是细胞因子家族的一部分。两大集团 趋化因子是C-X-C和C-C趋化因子和特异性趋化因子受体。 C-X-C和C-C趋化因子已被证明是HIV-1的重要共受体 HIV-2。我们现在已经证明，HIV-1感染单核细胞 导致C-X-C含量的显著增加 趋化因子白细胞介素-8（IL-8）和生长相关癌基因α（GRO-α）。我们有 还表明GRO-α的产生增加是由以下相互作用介导的： 病毒gp 120与CXCR 4和LL-8的刺激由gp 120介导， 病毒反式激活蛋白达特。然后IL-8和GRO-α都刺激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HIV-1的复制。 GRO-cx和IL-8是血管生成趋化因子，最近也显示 通过卡波济肉瘤疱疹病毒（KSHV）编码的 G蛋白偶联受体。我们的研究小组现在已经证明，GRO-α和IL-8 由KSHV感染的人内皮细胞产生，是主要的介质 在体外和小鼠模型中的血管生成。因此，我们的假设是 即KSHV感染内皮细胞，而HIV-1感染邻近 单核细胞，导致C-X-C水平的显著增加， 趋化因子GRO-α和IL-8，促进血管生成和KS的发展。 鉴于上述情况，我们现在建议进一步表征IL-8的作用 和GRO-α在KSHV的复制中以及在转化和血管生成中 KSHV感染的内皮细胞的潜力。此外，使用定量 图像单细胞分析，我们将检查是否在水平的变化， IL-8和/或GRO-α表达与KSHV复制相关，和/或 KS病变的形态学模式。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，生长因子， 和HIV/达特在KS发病机制中的作用，并提出新的途径， 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.