TY - JOUR
T1 - Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia
AU - Zheng, Jialin
AU - Thylin, Michael R.
AU - Ghorpade, Anuja
AU - Xiong, Huangui
AU - Persidsky, Yuri
AU - Cotter, Robin
AU - Niemann, Douglas
AU - Che, Myhanh
AU - Zeng, Yong Chun
AU - Gelbard, Harris A.
AU - Shepard, Robin B.
AU - Swartz, Jennifer M.
AU - Gendelman, Howard E.
N1 - Funding Information:
We thank Dr. James A. Hoxie for kindly providing the CXCR4 mAb 12G5; Drs. Pamela Carmines and Myron L. Toews for scientific discussion and technical suggestions; Ms. Julie Ditter, Robin Taylor, Lesley B. Gendelman and Lin Stowell for outstanding administrative and secretarial support; and Ms. Xiaojun Liu, Ms. Alicia Lopez, Ms. Jennifer Rasmussen and Mr. Walt Zink III for technical support. This work was supported in part by research grants (to H.E.G.) by the National Institutes of Health: P01 NS31492-01, R01 NS34239-01, 501 NS34239-02, R01 NS36126-01, and P01MH57556-01, Carter-Wallace, Cranbury, NJ and Glaxo-Wellcome, Research Triangle Park, NC and the Pediatrics AIDS Foundation. Dr. Anuja Ghorpade is an Elizabeth Glaser Pediatric AIDS Foundation Scholar.
PY - 1999/8/3
Y1 - 1999/8/3
N2 - The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1α (SDF-1α), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1α, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1α/β was detected predominantly in astrocytes and at low levels in MDM. SDF-1α/β was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1α induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD. Copyright (C) 1999 Elsevier Science B.V.
AB - The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1α (SDF-1α), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1α, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1α/β was detected predominantly in astrocytes and at low levels in MDM. SDF-1α/β was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1α induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD. Copyright (C) 1999 Elsevier Science B.V.
KW - CXCR4
KW - GTP binding protein
KW - HIV-1 associated dementia
KW - Monocyte-derived macrophages
KW - Neuronal apoptosis
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U2 - 10.1016/S0165-5728(99)00049-1
DO - 10.1016/S0165-5728(99)00049-1
M3 - Article
C2 - 10430052
AN - SCOPUS:0033046019
SN - 0165-5728
VL - 98
SP - 185
EP - 200
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
IS - 2
ER -