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Journal of Virology, June 2004, p. 6567-6584, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6567-6584.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion{dagger}

Michael D. Bobardt,1 Patrick Salmon,2 Lianchun Wang,3 Jeffrey D. Esko,3 Dana Gabuzda,4 Milan Fiala,5 Didier Trono,2 Bernadette Van der Schueren,6 Guido David,6 and Philippe A. Gallay1*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037,1 Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687,3 Department of Medicine, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073,5 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,4 Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland,2 Center for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium6

Received 9 December 2003/ Accepted 27 January 2004

As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

* Corresponding author. Mailing address: Department of Immunology, IMM-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8180. Fax: (858) 784-8227. E-mail: gallay{at}scripps.edu.

{dagger} This is publication no. 16230-IMM from the Department of Immunology, The Scripps Research Institute, La Jolla, Calif.

Journal of Virology, June 2004, p. 6567-6584, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6567-6584.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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