title: gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors.
abstract: To infect target cells, the human immunodeficiency virus (HIV) type I (HIV-1) must engage not only the well-known CD4 molecule, but it also requires one of several recently described coreceptors. In particular, the CXCR4 (LESTR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, whereas CCR5 is the major coreceptor used by primary HIV-1 strains that infect macrophages and CD4(+) T-helper cells (M-tropic viruses). In addition, the alpha chemokine SDF1alpha and the beta chemokines MIP1alpha, MIP1beta, and RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent soluble inhibitors of HIV infection by blocking the binding between the viral envelope glycoprotein gp120 and the coreceptors. Approximately two-thirds of individuals with acquired immunodeficiency syndrome (AIDS) show neurologic complications, which are referred to a syndrome called AIDS dementia complex or HIV-1-associated cognitive/motor complex. The HIV-1 coat glycoprotein gp120 has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the CNS. Furthermore, recent findings showing the presence of chemokine receptors on the surface of different cell types resident in the CNS raise the possibility that the association of gp120 with these receptors may contribute to the pathogenesis of neurological dysfunction. Here, we address the possible role of alpha and beta chemokines in inhibiting gp120-mediated neurotoxicity using the human neuroblastoma CHP100 cell line as an experimental model. We have previously shown that, in CHP100 cells, picomolar concentrations of gp120 produce a significant increase in cell death, which seems to proceed through a Ca(2+) - and NMDA receptor-dependent cascade. In this study, we gained insight into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein. We found that CHP100 cells constitutively express both CXCR4 and CCR5 receptors and that stimulation with phorbol 12-myristate 13-acetate down-regulates their expression, thus preventing gp120-induced cell death. Furthermore, all the natural ligands of these receptors exerted protective effects against gp120-mediated neuronal damage, although with different efficiencies. These findings, together with our previous reports, suggest that the neuronal injury observed in HIV-1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors.
authors.affiliation: Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Catani
authors.forename: M T
authors.initials: MT
authors.lastname: Corasaniti
authors.forename: M
authors.initials: M
authors.lastname: Navarra
authors.forename: G
authors.initials: G
authors.lastname: Nisticò
authors.forename: A
authors.initials: A
authors.lastname: Finazzi-Agrò
authors.forename: G
authors.initials: G
authors.lastname: Melino
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D000911:Antibodies, Monoclonal; D016923:Cell Death / Q000187:drug effects / Q000276:immunology*; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D015699:HIV Envelope Protein gp120; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D016194:Receptors, N-Methyl-D-Aspartate