PubMed · 9880966
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R Gosselin, M De Maeseneer, T Stadnik, M Osteaux. 1998. Multifocal leukoencephalopathy.. https://pubmed.ncbi.nlm.nih.gov/9880966/
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Inflammatory cytokines and enzymes such as IL-1 and inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of AIDS dementia, a condition associated with infection of the CNS cells by the HIV-1. In this report, we investigated the expression of iNOS, IL-1, and caspase-1 (interleukin-1 converting enzyme) in HIV-1 encephalitis (HIVE) by immunocytochemistry and analyzed their expression with respect to HIV-1 infection and glial activation. In HIVE, all three molecules were expressed at high levels in areas of HIV-1 infection (microglial nodules with HIV-1 p24 immunoreactivity) and in areas of diffuse white matter gliosis. Expression was cell-type specific, with IL-1 and caspase-1 being expressed in macrophages and microglia, and iNOS in activated astrocytes. Multinucleated giant cells, a hallmark of virally infected cells, showed intense staining for both IL-1 and caspase-1, suggesting induction of these molecules by HIV-1. Double immunocytochemistry demonstrated a regional co-localization of astrocyte iNOS and microglial IL-1 and caspase-1. These results support the notion that autocrine and paracrine interactions between HIV-1 infected macrophages and microglia, activated microglia, and astrocytes lead to expression of proinflammatory and neurotoxic molecules. iNOS and caspase-1 may provide additional therapeutic targets for HIVE.
The CX(3)C chemokine fractalkine was found to be up-regulated in the brain during inflammatory processes. In this study, we tried to assess the role of fractalkine in HIV-1-associated dementia. Fractalkine expression is up-regulated in the brains of AIDS patients with HAD. Fractalkine immunoreactivity was mainly detected in astrocytes. In addition, fractalkine expression was found to be up-regulated in cocultures of astrocytes and HIV-infected macrophages. This up-regulation was dependent on cell-cell contact. We propose that fractalkine produced during interactions between astrocytes and HIV-infected macrophages plays a role in HAD by regulating the trafficking of monocytic cells in the brain parenchyma.
Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.