Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Author:

Bobardt Michael D.1,Salmon Patrick2,Wang Lianchun3,Esko Jeffrey D.3,Gabuzda Dana4,Fiala Milan5,Trono Didier2,Van der Schueren Bernadette6,David Guido6,Gallay Philippe A.1

Affiliation:

1. Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

2. Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland

3. Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687

4. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

5. Department of Medicine, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073

6. Center for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium

Abstract

ABSTRACT 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.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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