Fibroblast growth factor modulates HIV coreceptor CXCR4 expression by neural cells

Recent studies suggest that the chemokine receptor CXCR4 may be involved in mediating the neurodegenerative process in the brains of patients with acq uired immunodeficiency disease (AIDS). In this context, we hypothesize that neurotrophic factors, such as fibroblast growth factor (FGF), might protec t against human immunodeficiency virus (HIV)-mediated neurotoxicity via reg ulating the expression of CXCR4 in neural cells. For this purpose, levels o f CXCR4 were determined in neuronal and glial cell lines after FGF1 and 2 t reatment. In addition, levels of CXCR4 immunoreactivity were associated wit h levels of FGF1 immunoreactivity in the brains of HIV-positive patients. T hese studies showed that neuronal CXCR4 levels decreased in a dose-dependen t manner after exposure to FGF. Conversely, glial CXCR4 was increased in a dose-dependent manner after FGF2 treatment. These effects were dependent on the FGF receptor tyrosine kinase signaling pathway, because FGF-induced ef fects on CXCR4 were blocked by the tyrosine kinase inhibitor, 5'-deoxy-5'-m ethylthioadenosine, or by anti-FGF receptor antibody. Stromal cell-derived factor-1, the ligand for CXCR4, and HIV gp120 neurotoxicity was attenuated by FGF1 in a dose-dependent manner in vitro, further supporting physiologic al relevance. In the brains of AIDS patients, the levels of neural CXCR4 im munoreactivity were inversely associated with FGF levels. Taken together, t hese results support the possibility that the neuroactive effects of FGF in HIV encephalitis might be mediated through regulation of the expression of CXCR4. J. Neurosci. Res. 59:671-679, 2000. (C) 2000 Wiley-Liss, Inc.