Show simple item record

dc.contributor.authorHurwitz, Arthur Andrew
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 55-02, Section: B, page: 3760.;Advisors: William D. Lyman; Joan W. Berman.
dc.description.abstractThe 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 the closely-associated astrocyte foot processes. We undertook two approaches to study the role of the BBB in human immunodeficiency virus type-1 (HIV)-infection of the CNS. In the first, the ability of HIV to infect endothelial cells (EC) was examined. In the second series of experiments, we characterized a tissue culture model of the BBB that consists of the co-culture of autologous EC and astrocytes and used it to examine the expression of adhesion molecules and chemokines by both the EC and astrocyte components of the BBB, and to characterize the interactions between HIV-infected monocytes and EC. The data presented in this thesis demonstrate that HIV infects neither EC expressing a transfected CD4 gene nor EC induced to express Fc receptors. We therefore based our subsequent studies on the idea that HIV enters the CNS as cell-associated virus rather than cell-free virus. In characterizing the BBB model, we demonstrated that astrocytes induce EC to express the BBB-specific markers GLUT-1 and {dollar}\gamma{dollar}-glutamyl transpeptidase and that the induction of these markers was dependent on the ability of astrocytes to come into contact with EC. Using this model, we showed that astrocytes also upregulate the expression of intercellular adhesion molecule 1 (ICAM-1) by EC. Western blot analysis demonstrated that ICAM-1 is also expressed in the developing human CNS. When exposed to the proinflammatory cytokine tumor necrosis factor {dollar}\alpha{dollar} (TNF), both EC and astrocytes expressed the adhesion proteins IG9, ICAM-1, vascular cell adhesion molecule 1 (VCAM) and E-selectin. In addition, astrocytes cultured alone expressed the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to both TNF and transforming growth factor {dollar}\beta{dollar}. Finally, using SEM and binding assays, we demonstrated that EC bind more HIV-infected monocytes than uninfected monocytes. Taken together, these data support the hypothesis that the BBB facilitates the entry of HIV-infected monocytes into the CNS. In addition to the increased interactions between infected monocytes and EC, 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. Future studies described herein will clarify further the role of the BBB in the neuropathogenesis of HIV infection.
dc.publisherProQuest Dissertations & Theses
dc.titleThe role of the blood-brain barrier in HIV infection of the CNS

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record