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
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.