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*
Cerebrovascular and Neuroscience Research Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Center for Neuroscience and Aging, Burnham Institute, La Jolla, CA 92037;
Departments of Pathology and Microbiology and Medicine, Center for Neurovirology and Neurodegenerative Disorders, and the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198; and
§
Eijkman-Winkler Institute, Section of Neuroimmunology, Utrecht, The Netherlands
Approximately one-quarter of individuals with AIDS develop
neuropathological symptoms that are attributable to infection of the
brain with HIV. The cognitive manifestations have been termed
HIV-associated dementia. The mechanisms underlying HIV-associated
neuronal injury are incompletely understood, but various studies have
confirmed the release of neurotoxins by macrophages/microglia infected
with HIV-1 or stimulated by viral proteins, including the envelope
glycoprotein gp120. In the present study, we investigated the
possibility that L-cysteine, a neurotoxin acting at the
N-methyl-D-aspartate subtype of glutamate
receptor, could contribute to HIV-associated neuronal injury. Picomolar
concentrations of gp120 were found to stimulate cysteine release from
human monocyte-derived macrophages (hMDM) in amounts sufficient to
injure cultured rat cerebrocortical neurons. TNF-
and IL-1ß, known
to be increased in HIV-encephalitic brains, as well as a cellular
product of cytokine stimulation, ceramide, were also shown to induce
release of cysteine from hMDM in a dose-dependent manner. A
TNF--neutralizing Ab and an IL-1ßR 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 cysteine than uninfected cells following
stimulation with TNF-. 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 macrophages but not
virus-infected macrophages. Such uninfected cells comprise the vast
majority of mononuclear phagocytes (macrophages and microglia) found in
HIV-encephalitic brains.
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