Transport of Human Immunodeficiency Virus Type 1 Pseudoviruses across the Blood-Brain Barrier: Role of Envelope Proteins and Adsorptive Endocytosis

Abstract

Blood-borne human immunodeficiency virus type 1 (HIV-1) crosses the blood-brain barrier (BBB) to induce brain dysfunction. How HIV-1 crosses the BBB is unclear. Most work has focused on the ability of infected immune cells to cross the BBB, with less attention devoted to the study of free virus. Since the HIV-1 coat glycoprotein gp120 can cross the BBB, we postulated that gp120 might be key in determining whether free virus can cross the BBB. We used radioactive virions which do (Env ؉ ) or do not (Env ؊ ) bear the envelope proteins to characterize the ability of HIV-1 to be taken up by the murine BBB. In vivo and in vitro studies showed that the envelope proteins are key to the uptake of free virus and that uptake was enhanced by wheat germ agglutinin, strongly suggesting that the envelope proteins induce viral adsorptive endocytosis and transcytosis in brain endothelia. Capillary depletion showed that Env ؉ virus completely crossed the vascular BBB to enter the parenchyma of the brain. Virus also entered the cerebrospinal fluid, suggesting passage across the choroid plexus as well. About 0.22% of the intravenously injected dose was taken up per g of brain. In vitro studies showed that postinternalization membrane cohesion (membrane binding not reversed with acid wash or cell lysis) was a regulated event. Intact virus was recovered from the brain endothelial cytosol and was effluxed from the endothelial cells. These results show that free HIV-1 can cross the BBB by an event related to adsorptive endocytosis and mediated by the envelope proteins.

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

“…3C). These data are in agreement with those of previous studies showing that envelope-deficient viruses exhibit an attenuated capacity to enter or transmigrate through BMECs (11,47). Since the gp160-deficient virus does not appear to cross the BMEC barrier, this suggests that the integrity of tight junctions was maintained and that the BMEC monolayer does not allow paracellular transport.…”

“…In one scenario, BMECs directly infected by HIV-1 release infectious particles into the brain (8,54,67,84). In an alternative scenario, HIV-1 enters BMECs from the blood, migrates through the cells, and is released into the CNS from the brain side of BMECs (10,11,47). In addition to these two transcellular routes, cell-free HIV-1 may also use a paracellular route via tight junctions (25) or by perforating the BMEC monolayer by inducing apoptosis (7,40,83).…”

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

“…Brain microvessel endothelial cells are a major component of the BBB and do not express CD4 receptor which HIV-1 uses to enter other cell types (Moses et al, 1993). Despite and absence of the CD4 receptor, HIV-1 can cross the BBB by two routes, the passage of cell free virus by adsorptive endocytosis (Banks et al, 2001) and the trafficking of infected immune cells across BBB (Persidsky et al, 1997). Both routes involve gp120, an HIV-1 envelope glycoprotein, expressed by HIV-1 infected immune cells.…”

High Frequency of Virus-Specific CD8+T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251

“…The central nervous system (CNS) is a target for many microbial and viral infections, including simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) (2,9,25,37,47). CNS infection occurs during primary SIV infection (7), and the degree of CNS pathology varies among animals (6,17,26,39,48).…”