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Review
, 15 (2), 111-22

Acquired Immunodeficiency Syndrome and the Blood-Brain Barrier

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Review

Acquired Immunodeficiency Syndrome and the Blood-Brain Barrier

Nathan S Ivey et al. J Neurovirol.

Abstract

The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency virus (SIV) in macaques. In this review, we provide an overview of the function, structure, and components of the BBB, followed by a more detailed discussion of the subcellular structures and regulation of the tight junction. We then discuss the ways in which HIV/SIV affects the BBB, largely through infection of monocytes/macrophages, and how infected macrophages crossing the BBB ultimately results in breakdown of the barrier.

Figures

Figure 1
Figure 1
The normal blood-brain barrier (left) is composed of multiple cell types. The tightly apposed brain microvascular endothelial cells (BMECs) joined by tight junctions play a major role. The role of the BMECs is augmented by perivascular macrophages, and foot processes of astrocytes and microglia that envelope the BMEC. Following HIV/SIV neuroinvasion (right), perivascular macrophages accumulate and this is associated with increases in BBB permeability associated with leaky TJs.
Figure 2
Figure 2
Occludin, Claudin-5, JAM-A and zo-1 are important tight junction associated proteins. Occludin, Claudin-5 and JAM-A span the intercellular gap of the tight junction and are anchored into the cell via zo-1 which in turn is bound to the actin cytoskeleton. Paracellular monocyte diapedesis involves traversing the tight junction via a series of interactions with integrin receptors at the luminal surface of a BMEC. This initiates highly regulated intracellular signaling that results in temporary opening of the TJ to allow the monocyte to pass into the perivascular space.
Figure 3
Figure 3
Infection of the central nervous system by SIV/HIV primarily involves cells of monocyte/macrophage lineage. HIV/SIV infection likely subverts the normal process of monocyte replacement of perivascular macrophages to cross the blood brain barrier. Some of these cells will be infected and carry the virus into the brain within days of infection. As the monocytes differentiate into macrophages they become a better substrate for viral replication and produce a variety of cytokines and chemokines. The cytokines and chemokines cause activation of various other cell types in the brain including endothelial cells, microglia and astrocytes. The endothelial cells upregulate adhesion molecules, which along with increased chemokine production facilitates further recruitment of leukocyte (primarily monocyte/macrophages) into the brain, giving rise to perivascular cuffs. Most of the cells in these cuffs are not infected by HIV/SIV but likely serve as fodder for further rounds of viral replication.
Figure 4
Figure 4
The tight junction between BMECs is composed of a matrix of dimeric transmembrane proteins including but not limited to occludin, claudin-5, and JAM-A that are likely to play a major role in the maintenance, regulation, and selectivity of the BBB. TJ proteins are anchored to the cytosol of BMECs by way of a protein complex comprised of zo proteins and others. This zo protein anchorage is bound to actin in the BMEC cytosol. When stimulated by pro-inflammatory cytokines, FAK, through MLCK and actin, causes redistribution of the zo-1 anchorage. Redistribution of zo-1 leads to tensile stress of the transmembrane proteins JAM, claudin-5, occludin and others which leads to opening of the tight junction and increased permeability of the BBB.
Figure 5
Figure 5
Paracellular diapedesis occurs when a circulating monocyte is bound by adhesion molecules (primarily ICAM-1 and ALCAM), and moves along a haptotactic adhesion gradient through the TJ. Occludin and claudin-5 (not shown) are also likely to have a role in extravasation.

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