TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier

Milan Fiala, David J. Looney, Monique Stins, Dennis D. Way, Ling Zhang, Xiaohu Gan, Francesco Chiappelli, Erik S. Schweitzer, Paul Shapshak, Martin E Weinand, Michael C. Graves, Marlys H Witte, Kwang Sik Kim

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)553-564
Number of pages12
JournalMolecular Medicine
Volume3
Issue number8
StatePublished - 1997

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Blood-Brain Barrier
HIV-1
Brain
Viruses
Permeability
Monocytes
Macrophages
Endothelial Cells
Infection
Pallor
Inulin
Viremia
Microglia
Viral Proteins
Encephalitis
Myelin Sheath
Dextrans
Fibronectins
Astrocytes
Cell Movement

ASJC Scopus subject areas

  • Genetics

Cite this

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.

TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier. / Fiala, Milan; Looney, David J.; Stins, Monique; Way, Dennis D.; Zhang, Ling; Gan, Xiaohu; Chiappelli, Francesco; Schweitzer, Erik S.; Shapshak, Paul; Weinand, Martin E; Graves, Michael C.; Witte, Marlys H; Kim, Kwang Sik.

In: Molecular Medicine, Vol. 3, No. 8, 1997, p. 553-564.

Research output: Contribution to journalArticle

Fiala, M, Looney, DJ, Stins, M, Way, DD, Zhang, L, Gan, X, Chiappelli, F, Schweitzer, ES, Shapshak, P, Weinand, ME, Graves, MC, Witte, MH & Kim, KS 1997, 'TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier', Molecular Medicine, vol. 3, no. 8, pp. 553-564.
Fiala M, Looney DJ, Stins M, Way DD, Zhang L, Gan X et al. TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier. Molecular Medicine. 1997;3(8):553-564.
Fiala, Milan ; Looney, David J. ; Stins, Monique ; Way, Dennis D. ; Zhang, Ling ; Gan, Xiaohu ; Chiappelli, Francesco ; Schweitzer, Erik S. ; Shapshak, Paul ; Weinand, Martin E ; Graves, Michael C. ; Witte, Marlys H ; Kim, Kwang Sik. / TNF-α Opens a Paracellular Route for HIV-1 Invasion across the Blood-Brain Barrier. In: Molecular Medicine. 1997 ; Vol. 3, No. 8. pp. 553-564.
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abstract = "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.",
author = "Milan Fiala and Looney, {David J.} and Monique Stins and Way, {Dennis D.} and Ling Zhang and Xiaohu Gan and Francesco Chiappelli and Schweitzer, {Erik S.} and Paul Shapshak and Weinand, {Martin E} and Graves, {Michael C.} and Witte, {Marlys H} and Kim, {Kwang Sik}",
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AU - Looney, David J.

AU - Stins, Monique

AU - Way, Dennis D.

AU - Zhang, Ling

AU - Gan, Xiaohu

AU - Chiappelli, Francesco

AU - Schweitzer, Erik S.

AU - Shapshak, Paul

AU - Weinand, Martin E

AU - Graves, Michael C.

AU - Witte, Marlys H

AU - Kim, Kwang Sik

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N2 - 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.

AB - 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.

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