Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain.
HIV-1 penetration of the brain is a pivotal event in the neuropathogenesis of AIDS-associated dementia. The establishment of productive viral replication or up-regulation of adhesion molecule expression on brain microvascular endothelial cells (BMVEC) could permit entry of HIV into the central nervous system. To investigate the contribution of both, we inoculated primary human BMVEC with high titer macrophage-tropic HIV-1 or cocultured them with virus-infected monocytes. In both instances, BMVEC failed to demonstrate productive viral replication. Cell to cell contact between monocytes and microvascular endothelium resulted in E-selectin expression on BMVEC. BMVEC. cocultured with LPS-activated HIV-infected monocytes expressed even higher levels of E-selectin and vascular cell adhesion molecule-1 (VCAM-1). Transwell assays supported a role of soluble factors, from virus-infected monocytes, for the induction of adhesion molecules on BMVEC. To verify the in vivo relevance of these findings, levels of adhesion molecules were compared with those of proinflammatory cytokines and HIV-1 gene products in brain tissue of AIDS patients with or without encephalitis and HIV-seronegative controls. E-Selectin, and to a lesser degree VCAM-1, paralleled the levels of HIV-1 gene products and proinflammatory cytokines in brain tissue of subjects with encephalitis. Most importantly, an association between macrophage infiltration and increased endothelial cell adhesion molecules was observed in encephalitic brains. Monocyte binding to encephalitic brain tissue was blocked with Abs to VCAM-1 and E-selectin. These data, taken together, suggest that HIV entry into brain is, in part, a consequence of the ability of virus-infected and immune-activated monocytes to induce adhesion molecules on brain endothelium.
Nottet
H S
HS
Department of Pathology, Eppley Institute for Cancer and Allied Disease, University of Nebraska Medical Center, Omaha 68198, USA.
Persidsky
Y
Y
Sasseville
V G
VG
Nukuna
A N
AN
Bock
P
P
Zhai
Q H
QH
Sharer
L R
LR
McComb
R D
RD
Swindells
S
S
Soderland
C
C
Gendelman
H E
HE
D001483:Base Sequence; D001921:Brain / Q000098:blood supply / Q000821:virology*; D002448:Cell Adhesion; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism*; D015658:HIV Infections / Q000209:etiology / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008262:Macrophage Activation; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000821:virology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology
D019040:E-Selectin; D019010:Vascular Cell Adhesion Molecule-1