Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors.
Central nervous system dysfunction is commonly observed in children with HIV-1 infection, but the mechanisms whereby HIV-1 causes encephalopathy are not completely understood. We have previously shown that human brain microvascular endothelial cells (HBMEC) from children are responsive to gp120 derived from X4 HIV-1 by increasing expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1. However, the mechanisms involved in gp120-mediated up-regulation of cell adhesion molecule expression is unclear. In the present study, we found that gp120 derived from both X4 and R5 HIV-1 induced increased expression of ICAM-1 on HBMEC, but the degree of this up-regulation differed among the various HBMEC isolates. The up-regulation of ICAM-1 was inhibited by anti-CD4 antibodies as well as by specific antibodies directed against chemokine receptors and small-molecule coreceptor inhibitors. Anti-CD4 antibodies inhibited the increase in ICAM-1 expression mediated by gp120 derived from X4 and R5 HIV-1, whereas antibodies against chemokine receptors displayed a differential inhibition depending on the source of gp120. Both X4 and R5 gp120-induced ICAM-1 expression was sensitive to pertussis toxin and involved the nuclear factor-kB pathway. These findings indicate a direct involvement of CD4 and a differential involvement of chemokine receptors in the activation of pediatric HBMEC by X4 and R5 gp120. The activation of brain endothelium of children by HIV-1 protein gp120 by way of CD4 and chemokine receptors may have implications for the pathogenesis of HIV-1 encephalopathy in the pediatric population.
Stins
Monique F
MF
Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA. mstins@jhmi.edu
Pearce
Donna
D
Di Cello
Francescopaolo
F
Erdreich-Epstein
Anat
A
Pardo
Carlos A
CA
Sik Kim
Kwang
K
D019138:Antibodies, Blocking / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008833:Microcirculation / Q000166:cytology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles; D009930:Organic Chemicals / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D019138:Antibodies, Blocking; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D013450:Sulfones; D018799:Intercellular Adhesion Molecule-1; D037342:Pertussis Toxin