Details

Autor(en) / Beteiligte

• Fiala, M
• Looney, D J
• Stins, M
• Way, D D
• Zhang, L
• Gan, X
• Chiappelli, F
• Schweitzer, E S
• Shapshak, P
• Weinand, M
• Graves, M C
• Witte, M
• Kim, K S

Titel

TNF-alpha opens a paracellular route for HIV-1 invasion across the blood-brain barrier

Ist Teil von

• Molecular medicine (Cambridge, Mass.), 1997-08, Vol.3 (8), p.553-564

Ort / Verlag

England: The Feinstein Institute for Medical Research

Erscheinungsjahr

1997

Quelle

MEDLINE

Beschreibungen/Notizen

• HIV-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-alpha. 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. Cell-free HIV-1 was retained by the blood-brain barrier with close to 100% efficiency. TNF-alpha 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. Early after the infection, the blood-brain barrier protects the brain from HIV-1. Immune mediators, such as TNF-alpha, 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.