title: Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion.
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.
authors.affiliation: Department of Immunology, IMM-9, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bobardt
authors.forename: Patrick
authors.initials: P
authors.lastname: Salmon
authors.forename: Lianchun
authors.initials: L
authors.lastname: Wang
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
authors.forename: Milan
authors.initials: M
authors.lastname: Fiala
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.forename: Bernadette
authors.initials: B
authors.lastname: Van der Schueren
authors.forename: Guido
authors.initials: G
authors.lastname: David
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Gallay
mesh_terms: D001812:Blood-Brain Barrier / Q000821:virology; D001921:Brain / Q000098:blood supply* / Q000821:virology*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D042783:Endothelial Cells / Q000821:virology; D004730:Endothelium, Vascular / Q000166:cytology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D011509:Proteoglycans / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D011509:Proteoglycans; D015728:Receptors, HIV; C036090:heparin proteoglycan; D006493:Heparin