A prime target of HIV is the CNS, with virus and infected immunocytes appearing in the CNS early in the course of infection and ADC presenting in most patients. How HIV enters the CNS is unknown but it must negotiate the blood-brain barrier (BBB) to do so. The goal of this research is to determine how HIV crosses the BBB and ultimately to develop therapeutic strategies for blocking passage. The BBB exists largely because the endothelial cells which comprise the capillary bed of the brain and the ependymal cells which define the choroid plexus are modified by intercellular tight junctions, a lack of intracellular pores, and a low rate of vesicular transcytosis. These modifications allow the BBB to severely restrict the entry of circulants into the CNS. The mechanism(s) of BBB/HIV interactions must account for 1) viral passage, 2) passage of infected immunocytes, and 3) the diffuse disruption of the BBB to serum proteins. The single known mechanism of BBB permeability that can account for all of these findings is adsorptive endocytosis (AE). AE is a response to pathological insults, including blood-borne toxic glycoproteins, in which vesicles derived from the luminal (blood side) BBB cell membrane are routed to lysosomes, the Golgi complex, and the abluminal (brain side) cell membrane. With more extreme insults, vesicles can coalesce to form canalicular structures that traverse the BBB. We hypothesize that gp120, the neurotoxic glycoprotein present on the surface of HIV and infected immunocytes, initiates AE. This hypothesis provides 1) a vesicular route for viral passage across the BBB, the route used by most viruses capable of crossing the BBB, 2) a canalicular mechanism for infected immunocytes which resembles the process used by uninfected immunocytes, 3) vesicular and canalicular pathways for the passage of serum proteins; that is, a mechanism for the disruption of the BBB, and 4) emphasizes gp120, an established mediator of viral entry into other cell types. The hypothesis that gp120 is the critical initiator of AE can be readily tested with viral/cell-free gp120. We propose to test this hypothesis by determining in vivo and in vitro how gp120 crosses the BBB. The experiments proposed, although presented as tests for AE, would also determine the extent that the other major pathways across the BBB (leakage at the BBB or BBB deficient areas; transmembrane diffusion; saturable transport systems) are involved in the entry of gp120 into the CNS. This assures that the current studies will likely result in new strategies for the development of therapeutics, such as inhibitors of AE, that prevent the entry of HIV into the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH054979-04
Application #
2675405
Study Section
Special Emphasis Panel (ZMH1-NRB-R (O2))
Program Officer
Rausch, Dianne M
Project Start
1995-09-30
Project End
2000-04-30
Budget Start
1998-08-01
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Banks, W A; Moinuddin, A; Morley, J E (2001) Regional transport of TNF-alpha across the blood-brain barrier in young ICR and young and aged SAMP8 mice. Neurobiol Aging 22:671-6
Banks, W A; Farr, S A; Butt, W et al. (2001) Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J Pharmacol Exp Ther 297:1113-21
Banks, W A; Freed, E O; Wolf, K M et al. (2001) Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol 75:4681-91
Mizushima, H; Nakamura, Y; Matsumoto, H et al. (2001) The effect of cardiac arrest on the blood-testis barrier to albumin, tumor necrosis factor-alpha, pituitary adenylate cyclase activating polypeptide, sucrose, and verapamil in the mouse. J Androl 22:255-60
Banks, W A; Phillips-Conroy, J E; Jolly, C J et al. (2001) Serum leptin levels in wild and captive populations of baboons (papio): implications for the ancestral role of leptin. J Clin Endocrinol Metab 86:4315-20
Banks, W A; King, B M; Rossiter, K N et al. (2001) Obesity-inducing lesions of the central nervous system alter leptin uptake by the blood-brain barrier. Life Sci 69:2765-73
Moinuddin, A; Morley, J E; Banks, W A (2000) Regional variations in the transport of interleukin-1alpha across the blood-brain barrier in ICR and aging SAMP8 mice. Neuroimmunomodulation 8:165-70
Maness, L M; Banks, W A; Kastin, A J (2000) Persistence of blood-to-brain transport of leptin in obese leptin-deficient and leptin receptor-deficient mice. Brain Res 873:165-7
Banks, W A; Farr, S A; Morley, J E (2000) Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse. J Gerontol A Biol Sci Med Sci 55:B601-6
Banks, W A; Clever, C M; Farrell, C L (2000) Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice. Am J Physiol Endocrinol Metab 278:E1158-65

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