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Originally published online as doi:10.2353/ajpath.2008.080045 on June 13, 2008

Published online before print June 13, 2008
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(American Journal of Pathology. 2008;173:130-143.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080045

YKL-40, a Marker of Simian Immunodeficiency Virus Encephalitis, Modulates the Biological Activity of Basic Fibroblast Growth Factor

Dafna Bonneh-Barkay*, Stephanie J. Bissel*, Gouji Wang*, Kenneth N. Fish{dagger}, Georgina C.B. Nicholl*, Samuel W. Darko*, Rafael Medina-Flores*, Michael Murphey-Corb{ddagger}, Premeela A. Rajakumar{ddagger}, Julia Nyaundi{ddagger}, John W. Mellors§, Robert Bowser* and Clayton A. Wiley*

From the Departments of Pathology,* Psychiatry,{dagger} Molecular Genetics and Biochemistry,{ddagger} and Medicine,§ University of Pittsburgh, Pittsburgh, Pennsylvania

Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival.






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Copyright © 2008 by the American Society for Investigative Pathology.