Virginia J. Sanders

Chemokines and receptors in HIV encephalitis

Background: Chemokines are involved in the migration of leukocytes and have been implicated in several inflammatory diseases of the central nervous system. Some of their receptors have been proposed to mediate HIV infection. Objective: To determine changes in chemokine and receptor expression in HIV encephalitis, and to determine whether upregulation leads to recruitment of infected monocytes across the blood‐brain barrier and participates in HIV neuropathology. Methods: Immunocytochemistry and double‐label immunofluorescent laser confocal microscopy was performed with antibodies to chemokines and their receptors on brain tissues from patients who died with or without HIV encephalitis. In vivo distribution was compared with in vitro cultures of human neuroglial cells. Results: The β‐chemokines monocyte chemotactic protein‐1, macrophage inflammatory protein‐1α, and RANTES were detected on brain macrophages. Their presence was associated with the histopathological signs of HIV encephalitis. The α‐chemokines IP‐10 (10 kDa inflammatory protein) and interleukin‐8 were expressed by astrocytes in all tissues, including controls. Presence of the CXC‐chemokine receptor (CXCR)‐4 was seen on brain macrophages/microglia, neurons, and astrocytes. CC‐Chemokine receptor (CCR)‐5 was detected only on macrophages/microglia. CCR‐3 and CCR‐1 were expressed by macrophages and endothelial cells. In vitro studies examining the presence of CCR‐3, CCR‐5, and CXCR‐4 on human brain cell cultures demonstrated abundant neuronal and microglial expression.Background:Chemokines are involved in the migration of leukocytes and have been implicated in several inflammatory diseases of the central nervous system. Some of their receptors have been proposed to mediate HIV infection.Objective:To determine changes in chemokine and receptor expression in HIV en

Expression of stromal cell-derived factor 1α protein in HIV encephalitis

Abstract Analysis of the patterns of stromal cell-derived factor 1α (SDF-1α) expression in the brains from HIV-positive patients suggests that in neuronal cells, SDF-1α might play a role in neuroprotection and neurite extension in response to HIV infection. In all cases analyzed, SDF-1α immunoreactivity was primarily present in astroglial cells. Patients with HIV encephalitis (HIVE) showed intense somato-dendritic neuronal SDF-1α immunoreactivity, while HIVE negative patients with neurodegeneration had a significant decrease in neuronal SDF-1α immunoreactivity. Neuronal cells treated with SDF-1α displayed increased neurite outgrowth. Similarly, neurons treated with HIV-Tat, which induced SDF-1α expression, also showed neurite outgrowth. Tat-mediated neurite outgrowth was blocked by anti-SDF-1α antibody. These results suggest that SDF-1α may play a role in the neuronal response to HIV in the brains of AIDS patients.

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 acquired immunodeficiency disease (AIDS). In this context, we hypothesize that neurotrophic factors, such as fibroblast growth factor (FGF), might protect against human immunodeficiency virus (HIV)‐mediated neurotoxicity via regulating the expression of CXCR4 in neural cells. For this purpose, levels of CXCR4 were determined in neuronal and glial cell lines after FGF1 and 2 treatment. In addition, levels of CXCR4 immunoreactivity were associated with levels of FGF1 immunoreactivity in the brains of HIV‐positive patients. These studies showed that neuronal CXCR4 levels decreased in a dose‐dependent 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 effects on CXCR4 were blocked by the tyrosine kinase inhibitor, 5′‐deoxy‐5′methylthioadenosine, 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 physiological relevance. In the brains of AIDS patients, the levels of neural CXCR4 immunoreactivity were inversely associated with FGF levels. Taken together, these 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

Neuron-enriched second trimester human cultures: growth factor response and in vivo graft survival.

Grafts of first trimester fetal tissue show limited survival and integration in the adult CNS. Alternative grafting strategies have been sought for treatment of neurodegenerative disease. We have developed cultures of human second trimester fetal tissues to study neuronal differentiation. Grafted into the SCID mouse striatum, aggregates of these cultures formed neuron-rich xenografts for at least 8 months. We examined the influence of various neurotrophic factors, including basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta 1 (TGF-β1), and hepatocyte growth factor (HGF), on the growth and differentiation of neuronal and glial cell populations. BDNF promoted the survival and differentiation of second trimester neurons whereas bFGF exhibited a strong proliferative effect on precursors and the astroglial population. Our data suggest that second trimester human fetal cultures contain neuroprogenitor cells that can be directed to the neuronal lineage. This process may be amplified by treatment with BDNF, which we hypothesize could improve the long-term in vivo survival of neuron-enriched grafts.