Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon.
The pathological correlates of dementia due to human immunodeficiency virus (HIV) infection are glial cell activation and cytokine dysregulation. These findings occur in the setting of small numbers of productively infected cells within the brain. We determined whether exposure of susceptible cells to Tat protein of HIV could result in the production of select proinflammatory cytokines. In a dose-responsive manner, Tat induced interleukin (IL)-1beta production in monocytic cells, while astrocytic cells showed an increase in mRNA for IL-1beta, but had a translation block for IL-1beta protein production. Conversely, IL-6 protein and mRNA productions were strongly induced in astrocytic cells and minimally in monocytic cells. IL-1beta and IL-6 production were independent of tumor necrosis factor-alpha production. An exposure to Tat for a few minutes was sufficient for sustained releases of cytokines for several hours. This prolonged cytokine production is likely maintained by a positive feed back loop of Tat-induced nuclear factor kappaB activation and cytokine production that is independent of extracellular calcium. Thus a transient exposure may be sufficient to initiate a cascade of events resulting in cerebral dysfunction and a "hit and run" approach may be in effect. Hence cross-sectional measurement of viral load in the brain may not be a useful indicator of the role of viral products in the neuropathogenesis of HIV dementia.
Nath
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Departments of Neurology, Microbiology, and Immunology, University of Kentucky, Lexington, Kentucky 40536-0284, USA. anath@pop.uky.edu
Conant
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Chen
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Scott
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D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D015696:Gene Products, tat / Q000494:pharmacology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D054322:tat Gene Products, Human Immunodeficiency Virus
D016207:Cytokines; D015696:Gene Products, tat; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D002118:Calcium