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

Mol Med. 1997 Aug;3(8):553-64.


Background: 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.

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-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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Astrocytes
  • Blood-Brain Barrier*
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology
  • Cell Culture Techniques
  • Cell Membrane Permeability
  • Cell Movement
  • Cells, Cultured
  • Child
  • Collagen
  • Electric Impedance
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / virology
  • Extracellular Matrix / virology
  • Fibronectins
  • HIV Core Protein p24 / metabolism
  • HIV-1 / pathogenicity*
  • Humans
  • Interleukin-6 / metabolism
  • Monocytes / virology
  • RNA, Viral / analysis
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Fibronectins
  • HIV Core Protein p24
  • Interleukin-6
  • RNA, Viral
  • Tumor Necrosis Factor-alpha
  • RMP 7
  • Collagen
  • Bradykinin