Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells.
Human immunodeficiency virus (HIV)-1 infection is often complicated with neurologic disorders, but the pathogenesis of HIV-1 encephalopathy is incompletely understood. Tat (HIV-1 transactivator protein) is released from HIV-1-infected cells and has been detected in the sera and cerebrospinal fluid of HIV-1-infected patients. Tat, along with increased inflammatory cytokines such as interferon-gamma (IFN-gamma), have been implicated in the pathogenesis of HIV-1-associated blood-brain barrier dysfunction. The present study examined the effects of Tat and IFN-gamma on human brain microvascular endothelial cells (HBMECs), which constitute the blood-brain barrier. Tat produced cytotoxicity of HBMECs, but required IFN-gamma. IFN-gamma treatment of HBMECs up-regulates vascular endothelial growth factor receptor-2 (VEGFR2/KDR), which is known to be the receptor for Tat. Tat activated KDR in the presence of IFN-gamma, and Tat-mediated cytopathic changes involve its interaction with KDR and phosphatidylinositol 3-kinase (PI3K). Further understanding and characterization of Tat-HBMEC interactions should help us understand HIV-1 neuropathogenesis and develop strategies to prevent HIV-1 encephalopathy.
Khan
Naveed Ahmed
NA
Division of Pediatric Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Di Cello
Francescopaolo
F
Nath
Avi
A
Kim
Kwang Sik
KS
D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000821:virology; D015696:Gene Products, tat / Q000235:genetics / Q000302:isolation & purification / Q000633:toxicity*; D015497:HIV-1; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology* / Q000821:virology*; D011994:Recombinant Proteins / Q000633:toxicity; D017384:Sequence Deletion; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma