BEHAVIORAL DISORDERS AND TNF CHANNELS IN AIDS

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Behavioral, cognitive, and motor disorders are clinical manifestations of AIDs Dementia Complex (ADC). ADC is likely mediated, at least in part, by the cytokines tumor necrosis factor alpha (TNF-alpha) and lymphotoxin (LT). TNF and LT are pleiotropic cytokines secreted by macrophages and lymphocytes. TNF and LT possess a broad range of hormonal and cytotoxic actions, but the mechanism of action of TNF and LT is unknown. Our laboratory has made the recent discovery that TNF and LT can form ion-permeable channels in planar lipid membranes, and we have proposed that channel formation may explain some physiologic effects of TNF such as the killing of tumor cells and the depolarization of muscle cells. Several lines of evidence implicate TNF in the pathophysiology of AIDS including the facts that TNF levels are elevated in AIDS patients, TNF can cause cachexia, TNF can increase HIV replication, and TNF can kill HIV-infected lymphocytes. TNF can increase HIV replication, and TNF can kill HIV-infected lymphocytes. TNF has also been found in the CSF of AIDS patients and its ability to depolarize cells and demyelinate nerve fibers may contribute to the dementia complex of AIDS (ADC). The broad goal of this research is to understand the role of these channels in the pathophysiology of AIDS and to search for ways to modify the destructive actions of TNF and LT in AIDS. TNF and LT channels will be characterized using electrophysiologic techniques in lipid bilayer and whole cells (patch clamp).