CULTURED AIDS-RELATED KAPOSIS-SARCOMA (AIDS-KS) CELLS DEMONSTRATE IMPAIRED BIOENERGETIC ADAPTATION TO OXIDANT CHALLENGE - IMPLICATION FOR OXIDANT STRESS IN AIDS-KS PATHOGENESIS

Despite its recognition as the most prevalent HIV associated cancer, s peculation still abounds regarding the pathogenesis of AIDS-related Ka posi's sarcoma (AIDS-KS). However, it has been established that both c ytokines, e.g. IL-6, and HIV-associated products, e.g., Tat, are integ ral in AIDS-KS cellular proliferation. Further, both experimental and clinical evidence is accumulating to link reactive oxygen intermediate s (ROI) with both cytokine induction (primarily via nuclear factor-kap pa B [NF-kappa B] dependent routes) as well as the subsequent cytokine , tumor necrosis factor a (TNF alpha) stimulation of HIV replication. Features of AIDS-KS patients, such as retention of phagocytes, presenc e of sustained immunostimulation, and a frequent history of KS lesions arising at traumatized sites, make oxidant stress a viable clinical f actor in AIDS-KS development. Time course nucleotide profile analyses show that AIDS-KS cells have an inherent, statistically significant, b iochemical deficit, even prior to oxidant stress, due to 1) a more gly colytic bioenergetic profile, resulting in lower levels of high energy phosphates (impairing capacity for glutathione [GSH] synthesis and DN A repair); 2) lower levels of NADPH (compromising the activities of GS SC reductase and peroxidase function of catalase); and 3) reduced leve ls of GSH (impeding both GSH peroxidase and GSH-S-transferases). Follo wing exposure to physiologically relevant levels of H2O2, only the hum an microvascular endothelial cells (a putative AIDS-KS progenitor cell ) responded with bioenergetic adaptations that reflected co-ordination of energy generating and cytoprotective pathways, e.g., retention of the cellular energy charge, increased NAD(+), and an accentuation of t he ATP, NADPH, and total adenine nucleotide differences relative to AI DS-KS cells. Also, some of the AIDS-KS strains retained intracellular GSSG subsequent to oxidant challenge, inviting the formation of delete rious protein mixed disulfides. While the results of our study address some AIDS-KS issues, they also raise an etiological question, i.e., D oes the inability to tolerate oxidant stress arise in conjunction with AIDS-KS neoplastic development, or is it pre-existing in the populati on at risk? Regardless, use of antioxidant therapy (low risk/potential ly high benefit) in both the ''at risk'' population as well as in thos e individuals with active disease may prove a useful preventative and/ or treatment modality. (C) 1995 Wiley-Liss, Inc.