ABSTRACT
The exact mechanism by which human immunodeficiency virus type 1 (HIV-1) produces dementia remains obscure. We have recently found that chemokines can inhibit neural progenitor cell proliferation. We hypothesized that HIV-1 could also inhibit neural progenitor cell proliferation by chemokine receptor signaling. We found that HIV-1 coat proteins that used C-C chemokine receptor 3 or C-X-C chemokine receptor 4 as coreceptors inhibited proliferation of neural progenitor cells in isolated cultures, as well as in hippocampal slices. The cerebrospinal fluid from patients with dementia also inhibited neural progenitor cell proliferation in these culture systems. To obtain an in vivo correlation, we examined hippocampus tissue obtained from patients with dementia at autopsy and found reduced numbers of neural progenitor cells in patients with dementia, compared with patients without dementia. Apolipoprotein E3, but not E4, antagonized the effects of coat proteins. We found reduced phosphorylation of extracellular signal-regulated kinase in neural progenitor cells treated with coat proteins, which may explain the protein's mechanism of action. We conclude that HIV-1 inhibits neural progenitor cell proliferation, which may result in impaired ability to form new memories and learn new tasks.
Subject(s)
AIDS Dementia Complex/pathology , Brain/pathology , Capsid Proteins/pharmacology , HIV-1/pathogenicity , Neurons/physiology , Stem Cells/physiology , AIDS Dementia Complex/virology , Apolipoprotein E3 , Apolipoprotein E4 , Apolipoproteins E/pharmacology , Astrocytes/cytology , Astrocytes/metabolism , Astrocytes/physiology , Brain/virology , Capsid Proteins/cerebrospinal fluid , Capsid Proteins/metabolism , Cell Count , Cell Differentiation , Cell Division/drug effects , Cell Line , Cerebrospinal Fluid/virology , Culture Techniques , Growth Inhibitors/pharmacology , HIV Envelope Protein gp120/metabolism , Hippocampus/pathology , Hippocampus/virology , Humans , Mitogen-Activated Protein Kinases/metabolism , Neurons/cytology , Neurons/metabolism , Phosphorylation , Receptors, CCR3 , Receptors, CXCR4/metabolism , Receptors, Chemokine/metabolism , Recombinant Proteins/pharmacology , Signal Transduction , Stem Cells/cytology , Stem Cells/metabolismABSTRACT
Many cell types in the brain express chemokines and chemokine receptors under homeostatic conditions, arguing for a role of these proteins in normal brain processes. Because chemokines have been shown to regulate hematopoietic progenitor cell proliferation, we hypothesized that chemokines would regulate neural progenitor cell (NPC) proliferation as well. Here we show that chemokines activating CXCR4 or CCR3 reversibly inhibit NPC proliferation in isolated cells, neurospheres, and in hippocampal slice cultures. Cells induced into quiescence by chemokines maintain their multipotential ability to form both neurons and astrocytes. The mechanism of chemokine action appears to be a reduction of extracellular signal-related kinase phosphorylation as well as an increase in Reelin expression. The inhibitory effects of chemokines are blocked by heparan sulfate and apolipoprotein E3 but not apolipoprotein E4, suggesting a regulatory role of these molecules on the effects of chemokines. Additionally, we found that the chemokine fractalkine promotes survival of NPCs. In addition to their role in chemotaxis, chemokines affect both the survival and proliferation of human NPCs in vitro. The presence of constitutively expressed chemokines in the brain argues that under homeostatic conditions, chemokines promote survival but maintain NPCs in a quiescent state. Our studies also suggest a link between inflammatory chemokine production and the inhibition of neurogenesis.
