AIDS is a severe, transmissible form of immune deficiency caused by infection with HIV. Several neoplasms are seen in greatly elevated frequency in AIDS and HIV infection. AIDS-KS is the most common AIDS- related malignancy. In autopsy surveys, it is seen in up to 60% of patients with HIV infection. Previous studies showed that IL-6 was important in the proliferation of AIDS-KS cells in vitro. For example, both IL-6 and the IL-6 receptor is found in cultured AIDS-Kaposi's sarcoma derived cells and in KS lesions in vivo. Direct modulation of the IL-6 pathway using oligonucleotides targeted to sequences within the IL-6 gene, IL-6 receptor gene, or the NF- IL-6 binding site of the IL-6 promotor decrease proliferation of AIDS-KS derived cells. Multiple cytokines (IL-1beta, TNF-alpha, Oncostatin-M) and the transactivating protein of HIV, tat, increase interleukin-6. Cytokines which decrease IL-6 production (rPF4, IL-4) decrease the proliferation of AIDS-KS cells in culture. This data suggests that IL-6 is an important factor in the growth of KS cells in vitro, that modulation of IL-6 expression or response in KS cells may be a common mode of action for multiple growth regulators and that interruption of the IL-6 pathway in vivo may have therapeutic potential. We will examine two defined aspects of the molecular pathogenesis of AIDS- associated Kaposi's sarcoma (AIDS-KS). Focusing on the roles of IL-6 and Oncostatin-M and using RNA and protein analysis, we will define the molecular factors involved in the up-regulation of IL-6 gene expression induced by HIV tat. Using cell cycle analysis, we will determine whether IL-6 acts as a programmed cell death (apoptosis) inhibiting factor for AIDS-KS cells. Using de novo HIV infection, primary cells, neutralizing antibodies, HIV-tat vectors, and transfection, we will determine if Oncostatin-M is the principal growth factor for AIDS-KS cells produced by retrovirus infected T Cells and monocytes and whether this increase in Oncostatin-M expression is a result of expression of retroviral transactivating factors. Finally, we will delineate the differences in expression and response to Oncostatin-M between normal, mesenchymal derived cells and AIDS-KS cells. We see if these differences are associated with alterations in patterns of membrane protein phosphorylation in AIDS-KS cells compared to normal, mesenchymal derived cells. These studies will help delineate the molecular pathogenesis of AIDS-KS and may provide new sites for therapeutic intervention.
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