Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of L-cysteine

Approximately one-quarter of individuals with AIDS develop neuropathologica l symptoms that are attributable to infection of the brain with HIV, The co gnitive manifestations have been termed HIV-associated dementia, The mechan isms underlying HIV-associated neuronal injury are incompletely understood, but various studies have, confirmed the release of neurotoxins by macropha ges/microglia infected with HIV-1 or stimulated by viral proteins, includin g the envelope glycoprotein gp120, In the present study, we investigated th e possibility that L-cysteine, a neurotoxin acting at the N-methyl-D-aspart ate subtype of glutamate receptor, could contribute to HN-associated neuron al injury. Picomolar concentrations of gp120 were found to stimulate cystei ne release from human monocyte-derived macrophages (hMDM) in amounts suffic ient to injure cultured rat cerebrocortical neurons, TNF-alpha and IL-1 bet a, known to be increased in HIV-encephalitic brains, as well as a cellular product of cytokine stimulation, ceramide, were also shown to induce releas e of cysteine from hMDM in a dose-dependent manner. A TNF-alpha-neutralizin g Ab and an IL-1 beta R antagonist partially blocked gp120-induced cysteine release, suggesting that these cytokines may mediate the actions of gp120. Interestingly, hMDM infected with HIV-1 produced significantly less cystei ne than uninfected cells following stimulation with TNF-alpha. Our findings imply that cysteine may play a role in the pathogenesis of neuronal injury in HIV-associated dementia due to its release from immune-activated macrop hages but not virus-infected macrophages, Such uninfected cells comprise th e vast majority of mononuclear phagocytes (macrophages and microglia) found in HIV-encephalitic brains. The Journal of Immunology, 2000, 164: 4265-427 0.