gp120 Induces Cell Death in Human Neuroblastoma Cells Through the CXCR4 and CCR5 Chemokine Receptors

Abstract

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 CD4ϩ T-helper cells (M-tropic viruses). In addition, the ␣ chemokine SDF1␣ and the ␤ chemokines MIP1␣, MIP1␤, 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 ␣ and ␤ 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 2ϩ -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. Key Words: HIV-1 gp120 -Chemokines-CXCR4 -CCR5-NMDA receptor.

Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization

“…Several studies have reported the neurotoxic effect of gp120 in vitro and in vivo and the involvement of chemokine receptors in this process (Catani et al, 2000;Hesselgesser et al, 1998;Kaul and Lipton, 1999;Meucci and Miller, 1996;Pandey and Bolsover, 2000;Zheng et al, 1999). In line with these reports, treatment of SH-SY5Y cells with gp120 IIIB (200 pM) resulted in significant, albeit moderate, cell death (Figure 1), which was blocked by pretreatment with AMD3100 (100 ng/ml).…”

“…CXCR4 is the specific receptor for the chemokine CXCL12 (previously known as SDF-1), which orchestrates the development of many areas of the brain as well as other tissues (Lazarini et al, 2003;Tran and Miller, 2003;Zou et al, 1998). CXCR4 can also bind the human immunodeficiency virus (HIV) envelope protein gp120 that induces apoptotic cell death in primary neurons and cell lines (Bachis and Mocchetti, 2004;Catani et al, 2000;Hesselgesser et al, 1997;Kaul and Lipton, 1999;Mattson et al, 2005;Meucci and Miller, 1996). Despite a convincing role of gp120 in the apoptosis of neurons, the effects of CXCL12 on neuronal survival remain controversial.…”

Mechanisms of apoptosis induction by the HIV-1 envelope

“…Soluble gp120 can induce apoptosis in lymphocytes, 12 but also in neurones, [24][25][26][27] cardiomyocytes, 17,28 kidney epithelial cells 29,30 and hepatocytes. 31 These potent cytotoxic effects have been implicated in the HIV-1-induced lymphodepletion, HIV-associated dementia (also called HIV encephalitis or neuro-AIDS), AIDS-cardiomyopathy, as well as AIDS associated nephropathy and hepatopathy.…”

Evidence for a role of glycosphingolipids in CXCR4‐dependent cell migration

“…This issue has been herein addressed having as an experimental model the human neuroepithelioma cell line CHP-100 [13]: CXCR4, in fact, is constitutively expressed by CHP-100 cells [14] and, in this system, it has been reported to mediate CXCL12-induced chemotaxis [8].…”