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Journal of Virology, July 2002, p. 6689-6700, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6689-6700.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Enters Brain Microvascular Endothelia by Macropinocytosis Dependent on Lipid Rafts and the Mitogen-Activated Protein Kinase Signaling Pathway

Nancy Q. Liu,1,2 Albert S. Lossinsky,3 Waldemar Popik,4 Xia Li,1 Chandrasekhar Gujuluva,1 Benjamin Kriederman,5 Jaclyn Roberts,1 Tatania Pushkarsky,6 Michael Bukrinsky,6 Marlys Witte,5 Martin Weinand,5 and Milan Fiala1,2*

Department of Medicine, Greater Los Angeles VA Medical Center Los Angeles, California 90073;,1 Cardiovascular Research Laboratory, UCLA School of Medicine, Los Angeles, California 90095,2 Neural Engineering Department, Huntington Medical Research Institutes, Pasadena, California 91105;,3 Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231,4 Department of Surgery, University of Arizona, Tucson, Arizona 85724,5 Department of Microbiology and Tropical Medicine, The George Washington University, Washington, D.C. 200376

Received 4 September 2001/ Accepted 27 March 2002

Brain microvascular endothelial cells (BMVECs) present an incomplete barrier to human immunodeficiency virus type 1 (HIV-1) neuroinvasion. In order to clarify the mechanisms of HIV-1 invasion, we have examined HIV-1 uptake and transcellular penetration in an in vitro BMVEC model. No evidence of productive infection was observed by luciferase, PCR, and reverse transcriptase assays. Approximately 1% of viral RNA and 1% of infectious virus penetrated the BMVEC barrier without disruption of tight junctions. The virus upregulated ICAM-1 on plasma membranes and in cytoplasmic vesiculotubular structures. HIV-1 virions were entangled by microvilli and were taken into cytoplasmic vesicles through surface invaginations without fusion of the virus envelope with the plasma membrane. Subsequently, the cytoplasmic vesicles fused with lysosomes, the virions were lysed, and the vesicles diminished in size. Upon cell entry, HIV-1 colocalized with cholera toxin B, which targets lipid raft-associated GM1 ganglioside. Cholesterol-extracting agents, cyclodextrin and nystatin, and polyanion heparin significantly inhibited virus entry. Anti-CD4 had no effect and the chemokine AOP-RANTES had only a slight inhibitory effect on virus entry. HIV-1 activated the mitogen-activated protein kinase (MAPK) pathway, and inhibition of MAPK/Erk kinase inhibited virus entry. Entry was also blocked by dimethylamiloride, indicating that HIV-1 enters endothelial cells by macropinocytosis. Therefore, HIV-1 penetrates BMVECs in ICAM-1-lined macropinosomes by a mechanism involving lipid rafts, MAPK signaling, and glycosylaminoglycans, while CD4 and chemokine receptors play limited roles in this process.

* Corresponding author. Mailing address: UCLA, CVRL, MRL 3645, 675 Young Dr. South, Los Angeles, CA 90095-1760. Phone: (310) 206-6392. Fax: (310) 825-1678. E-mail: fiala{at}ucla.edu.

Journal of Virology, July 2002, p. 6689-6700, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6689-6700.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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