gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors

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 o ne of several recently described coreceptors. In particular, the CXCR4 (LES TR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, wher eas 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 SDF1 alpha and the beta chemokines MIP1 alpha, MIP1 beta, a nd RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent solu ble inhibitors of HIV infection by blocking the binding between the viral e nvelope 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 compl ex 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 diff erent cell types resident in the CNS raise the possibility that the associa tion of gp120 with these receptors may contribute to the pathogenesis of ne urological dysfunction. Here, we address the possible role of alpha and bet a chemokines in inhibiting gpl20-mediated neurotoxicity using the human neu roblastoma CHP100 cell line as an experimental model. We have previously sh own that, in CHP100 cells, picomolar concentrations of gp120 produce a sign ificant increase in cell death, which seems to proceed through a Ca2+ and N MDA receptor-dependent cascade. In this study, we gained insight into the m echanism(s) of neurotoxicity elicited by the viral glycoprotein. We found t hat CHP100 cells constitutively express both CXCR4 and CCR5 receptors and t hat stimulation with phorbol 12-myristate 13-acetate down-regulates their e xpression, thus preventing gp120-induced cell death. Furthermore, all the n atural ligands of these receptors exerted protective effects against gpl20- mediated neuronal damage, although with different efficiencies. These findi ngs, together with our previous reports, suggest that the neuronal injury o bserved in HIV-1 infection could be due to direct (or indirect) interaction s between the viral protein gp120 and chemokine and/or NMDA receptors.