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


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.
Fiala
M
M
Department of Medicine, UCLA School of Medicine 90095-1769, USA. fiala@ucla.edu
Looney
D J
DJ
Stins
M
M
Way
D D
DD
Zhang
L
L
Gan
X
X
Chiappelli
F
F
Schweitzer
E S
ES
Shapshak
P
P
Weinand
M
M
Graves
M C
MC
Witte
M
M
Kim
K S
KS
D001253:Astrocytes; D001812:Blood-Brain Barrier; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D018929:Cell Culture Techniques; D002463:Cell Membrane Permeability; D002465:Cell Movement; D002478:Cells, Cultured; D002648:Child; D003094:Collagen; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000166:cytology / Q000821:virology; D005109:Extracellular Matrix / Q000821:virology; D005353:Fibronectins; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009000:Monocytes / Q000821:virology; D012367:RNA, Viral / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D005353:Fibronectins; D016655:HIV Core Protein p24; D015850:Interleukin-6; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; C089876:RMP 7; D003094:Collagen; D001920:Bradykinin