Background: HTV-1 invades the central nervous system early after infection when macrophage infiltration of the brain is low but myelin pallor is suggestive of blood-brain-barrier damage. High-level plasma viremia is a likely source of brain infection. To understand the invasion route, we investigated virus penetration across in vitro models with contrasting paracellular permeability subjected to TNF-α. Materials and Methods: Blood-brain-barrier models constructed with human brain microvascular endothelial cells, fetal astrocytes, and collagen I or fibronectin matrix responded in a dose-related fashion to cytokines and ligands modulating paracellular permeability and cell migration. Virus penetration was measured by infectious and quantitative HIV-1 RNA assays. Barrier permeability was determined using inulin or dextran. Results: Cell-free HIV-1 was retained by the blood-brain barrier with close to 100% efficiency. TNF-α increased virus penetration by a paracellular route in a dose-dependent manner proportionately to basal permeability. Brain endothelial cells were the main barrier to HIV-1. HIV-1 with monocytes attracted monocyte migration into the brain chamber. Conclusions: Early after the infection, the blood-brain barrier protects the brain from HIV-1. Immune mediators, such as TNF-α, open a paracellular route for the virus into the brain. The virus and viral proteins stimulate brain microglia and macrophages to attract monocytes into the brain. Infiltrating macrophages cause progression of HIV-1 encephalitis.
CITATION STYLE
Fiala, M., Looney, D. J., Stins, M., Way, D. D., Zhang, L., Gan, X., … Kim, K. S. (1997). TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier. Molecular Medicine, 3(8), 553–564. https://doi.org/10.1007/bf03401701
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