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The Journal of Neuroscience, January 25, 2006, 26(4):1098-1106; doi:10.1523/JNEUROSCI.3863-05.2006
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Neurobiology of Disease
CCL2/Monocyte Chemoattractant Protein-1 Mediates Enhanced Transmigration of Human Immunodeficiency Virus (HIV)-Infected Leukocytes across the Blood–Brain Barrier: A Potential Mechanism of HIV–CNS Invasion and NeuroAIDS
Eliseo A. Eugenin,1
Kristin Osiecki,2
Lillie Lopez,1
Harris Goldstein,2
Tina M. Calderon,1 and
Joan W. Berman1,2
1Departments of Pathology and 2Microbiology/Immunology, Albert Einstein College of Medicine, Bronx, New York 10461
Correspondence should be addressed to Dr. Joan W. Berman, Department of Pathology, F727, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Email: berman{at}aecom.yu.edu
Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood–brain barrier (BBB) disruption, and eventual loss of neurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity. We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1 , or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.
Key words: chemokines; cell trafficking; monocytes; blood–brain barrier; NeuroAIDS; macrophage-monocytes; HIV
Received Sept. 12, 2005;
revised Oct. 31, 2005;
accepted Dec. 6, 2005.
Correspondence should be addressed to Dr. Joan W. Berman, Department of Pathology, F727, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Email: berman{at}aecom.yu.edu
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