HIV-1 promotes quiescence in human neural progenitor cells.
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.
Krathwohl
Mitchell D
MD
Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. krath001@umn.edu
Kaiser
Jodi L
JL
D015526:AIDS Dementia Complex / Q000473:pathology* / Q000821:virology; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000473:pathology* / Q000821:virology; D036022:Capsid Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000494:pharmacology*; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002555:Cerebrospinal Fluid / Q000821:virology; D046508:Culture Techniques; D006131:Growth Inhibitors / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity*; D006624:Hippocampus / Q000473:pathology / Q000821:virology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D054397:Receptors, CCR3; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; C515350:CCR3 protein, human; D036022:Capsid Proteins; D006131:Growth Inhibitors; D015699:HIV Envelope Protein gp120; D054397:Receptors, CCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D020928:Mitogen-Activated Protein Kinases