TY - JOUR
T1 - HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection
AU - Kaul, M.
AU - Ma, Q.
AU - Medders, K. E.
AU - Desai, M. K.
AU - Lipton, S. A.
N1 - Funding Information:
Acknowledgements. We thank Dr. Timothy Springer, Center for Blood Research, Harvard Medical School, for CXCR4 KO mice, Dr. Murat Digicaylioglu for helpful discussions, and Lida Sionit, Helen Fang, Julie Wilson and Kenny Venegas for expert technical assistance. We are grateful to Drs. J Han (The Scripps Research Institute) and K Walsh (St. Elizabeth’s Medical Center, Tufts University School of Medicine) for providing adenoviral vectors. This work was supported in part by amfAR and by NIH Grants R01 NS050621 (to MK), and P01 HD29587, R01 EY09024, and R01 NS41207 (to SAL).
PY - 2007/2
Y1 - 2007/2
N2 - The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1β and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca2+ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca2+. This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.
AB - The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1β and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca2+ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca2+. This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.
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U2 - 10.1038/sj.cdd.4402006
DO - 10.1038/sj.cdd.4402006
M3 - Article
C2 - 16841089
AN - SCOPUS:33846217344
SN - 1350-9047
VL - 14
SP - 296
EP - 305
JO - Cell death and differentiation
JF - Cell death and differentiation
IS - 2
ER -