C-X-C Chemokines and Kaposi's Sarcoma

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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.