HIV- I infection of the central nervous system (CNS) has been demonstrated to be an early event after initial exposure, leading to common and serious brain dysfunction such as HIV- I encephalopathy. At present, the underlying pathogenesis of how HIV-1 enters the CNS and causes encephalopathy is not completely understood. The overall objective of this proposal is to determine whether HIV-1 or HIV-1 proteins can modulate brain endothelial cells and may enhance traversal of (HIV-1 infected) monocyte / macrophages into CNS, thereby perpetuating HIV-1 encephalopathy. HIV-1 may enter the brain by directly infecting brain endothelium, by crossing endothelium via absorbtive endocytosis, or via transcytosis of HIV-1 infected monocyte/ macrophages. Once HIV-1 is inside the CNS, it can trigger a cascade of events contributing to neurotoxicity and enhancing the immunopathological process. Since brain endothelium is a critical barrier to pathogens such as HIV- 1, it is critical to understand its role in HIV- I CNS infection. To this end, we have isolated and characterized human brain microvascular endothelial cells (HBMEC) and created an in vitro model of the (BBB) blood brain barrier by cultivating HBMEC on semipermeable tissue culture inserts. We showed that HIV- I envelope glycoprotein gpl2O, which is shed into the circulation of HIV- I infected patients is able to activate HBMEC, e.g., increase VCAM-1, ICAM-1 expression, PECAM-1 phosphorylation, monolayer permeability and monocyte transmigration. The proposed experiments are designed to further dissect the possible mechanisms of HIV-1 traversal across the blood brain barrier. This application is in response to RFA MH-00-010 to investigate mechanisms of HIV-1 trafficking in the CNS.
Specific aims are as follows: 1-To further assess in vitro models of the human blood brain barrier. 2-To characterize the in vitro human BBB model in response to HIV-1. 3-To examine whether HIV-1 enhances traversal of monocytes across in vitro model of the human BBB. By characterizing the individual steps involved in entry of monocytes into the brain, a better understanding of the pathogenesis of HIV-1-1 encephalopathy will be obtained and strategies may be developed to halt this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063850-02
Application #
6530932
Study Section
Special Emphasis Panel (ZMH1-NRB-A (02))
Program Officer
Joseph, Jeymohan
Project Start
2001-03-01
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$163,500
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chang, Yun C; Stins, Monique F; McCaffery, Michael J et al. (2004) Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier. Infect Immun 72:4985-95
Grab, Dennis J; Nikolskaia, Olga; Kim, Yuri V et al. (2004) African trypanosome interactions with an in vitro model of the human blood-brain barrier. J Parasitol 90:970-9
Stins, Monique F; Pearce, Donna; Choi, HeeJung et al. (2004) CD4 and chemokine receptors on human brain microvascular endothelial cells, implications for human immunodeficiency virus type 1 pathogenesis. Endothelium 11:275-84
Stins, Monique F; Pearce, Donna; Di Cello, Francescopaolo et al. (2003) Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors. Lab Invest 83:1787-98