MODEL FOR MONOCYTE MIGRATION THROUGH THE BLOOD-BRAIN-BARRIER DURING HIV-1 ENCEPHALITIS

Citation
Y. Persidsky et al., MODEL FOR MONOCYTE MIGRATION THROUGH THE BLOOD-BRAIN-BARRIER DURING HIV-1 ENCEPHALITIS, The Journal of immunology, 158(7), 1997, pp. 3499-3510
Citations number
60
Categorie Soggetti
Immunology
Journal title
The Journal of immunology
ISSN journal
00221767 → ACNP
Volume
158
Issue
7
Year of publication
1997
Pages
3499 - 3510
Database
ISI
SICI code
0022-1767(1997)158:7<3499:MFMMTT>2.0.ZU;2-V
Abstract
HIV-1 invades the central nervous system early during viral infection, but neurologic impairment usually occurs years later. The strongest p redictor for clinical dementia is the absolute numbers of immunocompet ent brain macrophages. Thus, how monocytes penetrate the brain during disease remains critical for understanding the neuropathogenic mechani sms of HIV-1 encephalitis. To these ends, we constructed an artificial blood-brain barrier (BBB) consisting of a matrix-coated membrane with brain microvascular endothelial cells (BMVEC) on one side and astrocy tes on the other. Astrocyte endfeet contacted the monolayer of BMVEC t hat formed tight junctions. To determine the role of viral and immune factors in monocyte penetration across the BBB, HIV-infected or uninfe cted monocytes with or without immune stimulation were placed onto the upper chamber of the BBB model system. Placement of immune-stimulated (LPS-treated) cells onto the BBB construct elicited gaps between BMVE C, with bulging of nuclear zones and increased numbers of vesicular Go lgi complexes and endoplasmic reticulum. This correlated with a profou nd increase (up to 20-fold) in the number of migrating cells. Viral in fection did not enhance monocyte migration. The activated monocytes sh owed increased numbers of philopodia, lysosomes, and vesicular Golgi c omplexes and expressed large levels of proinflammatory cytokines (TNF- alpha, IL-6, and IL-10). These data suggest that a major mechanism for the transendothelial migration of monocytes during HIV encephalitis i s the immune activation that accompanies viral infection of the centra l nervous system.