title: HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection.
abstract: 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-1beta 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.
authors.affiliation: Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. mkaul@burnham.org
authors.forename: M
authors.initials: M
authors.lastname: Kaul
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.forename: K E
authors.initials: KE
authors.lastname: Medders
authors.forename: M K
authors.initials: MK
authors.lastname: Desai
authors.forename: S A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D054377:Chemokine CXCL12; D016207:Cytokines / Q000633:toxicity; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D016202:N-Methylaspartate / Q000633:toxicity; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000473:pathology* / Q000821:virology; D009498:Neurotoxins / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D019713:Receptors, CCR5 / Q000172:deficiency / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D054377:Chemokine CXCL12; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007093:Imidazoles; D008024:Ligands; D009498:Neurotoxins; D011725:Pyridines; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D016202:N-Methylaspartate; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580