INTERACTION OF HIV-1 WITH THE VASCULAR ENDOTHELIUM

Project: Research project

Project Details

Description

We have developed a model of the human blood-brain barrier (BBB) using
autologous endothelial cells (EC) and astrocytes obtained from human
fetuses. This model system has provided information about the functioning
of the BBB during inflammatory conditions. It has also permitted the
development of new hypotheses about how BBB EC may play a pivotal role in
the pathogenesis of HIV CNS disease. Our focus is on the expression of EC
adhesion molecules and the role of cytokines in this process. An
understanding of these issues will provide information about the
underlying pathologic mechanisms of CNS disease during HIV infection and
may present a strategy to interrupt the process. The specific hypothesis
to be tested in this proposal is that adhesion molecule expression by BBB
EC facilitates the binding, and subsequent extravasation into the CNS
parenchyma, of HIV-infected cells. Additionally, the adhesion of infected
cells to the vasculature may result in EC infection. The role of adhesion
molecules expressed by EC during inflammatory conditions is now
recognized. Also, a role for adhesion molecules expressed by EC in the
pathogenesis of AIDS has been suggested. However, the definition of a role
for adhesion molecules in CNS disease during fetal HIV infection and
pediatric AIDS remains to be established. This proposal is designed to
investigate our hypothesis by using cell and molecular biologic techniques
combined with microscopy and immunocytochemistry. The following studies
will be conducted: 1) to characterize further this model of the BBB with
respect to its structural properties, adhesion molecule expression, and
the role of cytokines and HIV as inducers of adhesion molecules; 2) to
determine whether the adhesion molecules under study in the BBB model
system are expressed in vivo 3) to determine the mechanisms of binding and
transmigration of HIV-infected and noninfected mononuclear cells through
the BBB using this model, 4) to determine whether EC, cocultured with
autologous astrocytes, can be infected with cell-associated virus; 5) to
examine the effect of HIV, either cell-associated or cell-free, on the
structure and function of EC in this co-culture model; and, 6) to examine
the induction of cytokine expression by cells of this model in response to
exogenous cytokines, HIV-infected mononuclear cells or cell-free virus.
StatusFinished
Effective start/end date9/30/948/31/95

Funding

  • National Institute of Mental Health

ASJC

  • Infectious Diseases

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