THE ROLE OF THE BLOOD-BRAIN-BARRIER IN HIV-INFECTION OF THE CENTRAL-NERVOUS-SYSTEM

The blood-brain barrier (BBB) functions to regulate the entry of macromolecules, microbial pathogens, and circulating leukocytes into the central nervous system (CNS). It consists, in part, of the microvascular endothelium and associated astrocyte foot processes, found in close apposition to the abluminal side of the vascular endothelial cells (EC). During the pathogenesis of certain nervous system diseases with inflammatory components, the BBB may function to facilitate the entry of leukocytes into the CNS parenchyma. A common histologic observation in human immunodeficiency virus type-1 (HIV) encephalitis is the localization of HIV proteins to multinucleated giant cells that co-immunolabel with antibodies specific for cells of the monocyte/macrophage lineage, suggesting that HIV can enter the CNS as cell-associated virus. We previously characterized a tissue culture model of the BBB that consists of the co-culture of autologous EC and astrocytes. In this presentation, we used this model to examine the expression of adhesion molecules by both the EC and astrocyte components of this BBB model, and to characterize the interactions between HIV-infected monocytes and EC. The data presented in this review of our work demonstrates that astrocytes upregulate the expression of intercellular adhesion molecule (ICAM-1) by EC, In a parallel study, western blot analysis demonstrated that ICAM-1 is also expressed in the developing human CNS. When exposed to the proinflammatory cytokine tumor necrosis factor a (TNF), both EC cocultured with astrocytes and astrocytes cultured alone expressed the adhesion proteins IG9, ICAM-1, vascular cell adhesion molecule 1 (VCAM) and E-selection. Finally, using scanning electron microscopy (SEM) and binding assays, we demonstrated that EC bind more HIV infected monocytes then uninfected monocytes. Taken together, these data support the hypothesis that the BBB may participate in the entry of HIV infected monocytes into the CNS. In addition to the increased interactions between infected monocytes and EC (as suggested by increased adhesion between the two cell types in binding assays), adhesion molecules expressed by the BBB endothelium and chemokine expression by astrocytes and EC may contribute to the extravasation of HIV infected monocytes into the CNS parenchyma. Once inside the CNS, adhesion molecules expressed by astrocytes may serve to facilitate the migration of leukocytes to the site of inflammation.