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Background: Human immunodeficiency virus (HIV) leucoencephalopathy (HIVL) is an uncommon and rapidly progressive form of AIDS dementia complex (ADC) that has remained poorly understood. Tumour necrosis factor α (TNFα), which has been implicated in the pathogenesis of ADC, is predominantly localised in macrophages in the HIV infected brain, although in vitro studies indicate that neurones can express this cytokine. Objective: To examine the clinical/neuroradiological features of HIVL and the expression of TNFα in HIVL. Methods: Six patients who presented with rapidly progressive dementia within four to 12 weeks of the primary manifestation of their HIV infection were evaluated. Clinical history, treatment regimens, and imaging studies were reviewed, and brain samples from three of the patients were studied by means of immunohistochemistry. Results: Imaging studies showed diffuse bilateral deep white matter changes in all six patients. Clinical and imaging abnormalities improved in five of the six patients within weeks after initiation of antiretroviral treatment. Brain biopsies of two showed pronounced microglia/macrophage activation, but only scant viral protein (gp41) expression. Staining for TNFα was found in microglia/macrophages, and surprisingly, in neurones also. Postmortem analysis of a third patient also showed TNFα expression in neurones of the frontal cortex and basal ganglia. Conclusion: This study provides the first demonstration of staining for TNFα in the neurones of the HIV infected brain, and suggests that the process underlying this rapidly progressive form of ADC may reflect indirect mechanisms mediated by host factors, particularly TNFα.