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

Abstract

The chemokine receptor CXCR4 functions as human immunodeficiency virus (HIV)-1 coreceptor and is involved in acquired immunodeficiency virus (AIDS) neuropathogenesis. CXCR4 is expressed by most cell types in the brain, including microglia, astrocytes, and neurons. Studies have shown that the HIV envelope protein gp120 binds to neuronal CXCR4 and activates signal transduction pathways leading to apoptosis. However, the natural CXCR4 ligand (CXCL12) has been referred to induce both neuronal survival and death. Here the authors used flow cytometry to determine whether gp120 and CXCL12 differ in their ability to induce CXCR4 internalization in the human neuroblastoma cells SH-SY5Y, which constitutively express CXCR4. As expected, increasing concentration of CXCL12 reduced surface expression of CXCR4 in a time-and concentration-dependent manner. Conversely, gp120_IIIB (monomeric or oligomeric, in presence or absence of soluble CD4) did not change CXCR4 membrane levels. Similar results were obtained in a murine lymphocyte cell line (300-19) stably expressing human CXCR4. Nevertheless, gp120_IIIB was still able to activate intracellular signaling and proapoptotic pathways, via CXCR4. These results show that gp120_IIIB toxicity and signaling do not require CXCR4 internalization in SH-SY5Y cells, and suggest that the viral protein may alter normal CXCR4 trafficking thus, interfering with activation of prosurvival pathways. Journal of NeuroVirology (2006) 12, 211–218.

Keywords:

• cell death
• chemokine
• CXCL12
• CXCR4
• GPCRs
• signaling

Abbreviations used:
HIV,	=	Human Immunodeficiency Virus;
AIDS,	=	acquired immune deficiency syndrome;
gp120,	=	glycoprotein 120KDa,
GPCRs,	=	G protein-coupled receptors;
PI3K,	=	phosphoinositide-3 kinase;
AKT,	=	serine/threonine kinase AKT/PKB;
ERK,	=	extracellular signal-regulated kinase.

Abbreviations used:
HIV,	=	Human Immunodeficiency Virus;
AIDS,	=	acquired immune deficiency syndrome;
gp120,	=	glycoprotein 120KDa,
GPCRs,	=	G protein-coupled receptors;
PI3K,	=	phosphoinositide-3 kinase;
AKT,	=	serine/threonine kinase AKT/PKB;
ERK,	=	extracellular signal-regulated kinase.

The following reagent was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 SF2 gp120 from Chiron Corporation. This work was supported by the NIH grants DA15014 and DA19808 to OM. JP was partially supported by an NRSA fellowship (DA-020234).