HIV-1 gp120 proteins and gp160 peptides are toxic to brain endothelial cells and neurons: possible pathway for HIV entry into the brain and HIV-associated dementia.
Breakdown of the blood-brain barrier is commonly seen in patients with human immunodeficiency virus (HIV)-associated dementia, despite the lack of productive HIV-infection of the brain endothelium. Through this damaged blood-brain barrier, HIV and HIV-infected monocytes/macrophages infiltrate the brain and further infect microglia and brain macrophages. Neuronal cell death and dysfunction are the underlying cause of HIV-associated dementia, but no productive HIV-infection of neurons has been documented. It is likely that secreted viral products play a major role in blood-brain barrier damage and neuronal cell death. The aim of the present study was to examine the effect of HIV-1 gp160 peptides and gp120 proteins on brain microvascular endothelial cells and neurons from both human and rats. Four of the 7 gp160 peptides tested evoked significant neurotoxicity. Two different full-length recombinant HIV gp120 proteins (HIV-1CM235 gp120 and HIV-1MN gp120) also induced neuronal and brain endothelial cell death, and concentrations as little as 1 ng/ml evoked pronounced morphological changes in these cells and marked cytotoxicity. This study suggests that HIV proteins and peptides that are shed in vivo may be directly involved in blood-brain barrier damage and neuronal cell death in HIV-associated dementia.
Kanmogne
Georgette D
GD
Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City 73104, USA.
Kennedy
R C
RC
Grammas
Paula
P
D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D005333:Fetus; D015699:HIV Envelope Protein gp120 / Q000378:metabolism* / Q000633:toxicity; D019302:HIV Envelope Protein gp160 / Q000378:metabolism* / Q000633:toxicity; D015497:HIV-1 / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000633:toxicity
D017077:Culture Media, Conditioned; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins