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The Journal of Neuroscience, December 15, 1999, 19(24):10948-10965

Cytomegalovirus Cell Tropism, Replication, and Gene Transfer in Brain

Anthony N. van den Pol¹, Edward Mocarski³, Noah Saederup³, Jeffrey Vieira⁴, and Timothy J. Meier²

¹ Department of Neurosurgery, Yale University Medical School, New Haven, Connecticut 06520, Departments of ² Biological Science and ³ Microbiology and Immunology, Stanford University, Stanford, California 94305, and ⁴ Department of Laboratory Medicine , University of Washington, Seattle, Washington 98109

Cytomegalovirus (CMV) infects a majority of adult humans. During early development and in the immunocompromised adult, CMV causes neurological deficits. We used recombinant murine cytomegalovirus (mCMV) expressing either green fluorescent protein (GFP) or -galactosidase under control of human elongation factor 1 promoter or CMV immediate early-1 promoter as reporter genes for infected brain cells. In vivo and in vitro studies revealed that neurons and glial cells supported strong reporter gene expression after CMV exposure. Brain cultures selectively enriched in either glia or neurons supported viral replication, leading to process degeneration and cell death within 2 d of viral exposure. In addition, endothelial cells, tanycytes, radial glia, ependymal cells, microglia, and cells from the meninges and choroid were infected. Although mCMV showed no absolute brain cell preference, relative cell preferences were detected. Radial glia cells play an important role in guiding migrating neurons; these were viral targets in the developing brain, suggesting that cortical problems including microgyria that are a consequence of CMV may be caused by compromised radial glia. Although CMV is a species-specific virus, recombinant mCMV entered and expressed reporter genes in both rat and human brain cells, suggesting that mCMV might serve as a vector for gene transfer into brain cells of non-murine species. GFP expression was sufficiently strong that long axons, dendrites, and their associated spines were readily detected in both living and fixed tissue, indicating that mCMV reporter gene constructs may be useful for labeling neurons and their pathways.

Key words: virus; neuron; GFP; development; mouse CMV; gene therapy; neuropathology

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192410948-18$05.00/0

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