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Journal of Virology, November 2009, p. 11540-11549, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.02558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Peripheral Immunization Blocks Lethal Actions of Vesicular Stomatitis Virus within the Brain{triangledown}

Koray Ozduman, Guido Wollmann, Sebastian A. Ahmadi, and Anthony N. van den Pol*

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Received 11 December 2008/ Accepted 24 August 2009

Vesicular stomatitis virus (VSV) is the prototype virus for 75 or more negative-strand RNA viruses in the rhabdovirus family. Some of these viruses, including VSV, can cause neurological impairment or death upon brain infection. VSV has shown promise in the prevention and treatment of disease as a vaccine vector and an oncolytic virus, but infection of the brain remains a concern. Three VSV variants, the wild-type-related VSV-G/GFP and two attenuated viruses, VSV-CT1 and VSV-CT9-M51, were compared for neuroinvasiveness and neuromorbidity. In nonimmunized mice, direct VSV-G/GFP injection into the brain invariably resulted in lethal encephalitis; in contrast, partial survival was seen after direct injection of the attenuated VSV strains. In addition, both attenuated VSV strains showed significantly reduced neuroinvasiveness after intranasal inoculation of young postnatal day 16 mice. Of the three tested variants, VSV-CT9-M51 generated the lowest degree of neuropathology. Despite its attenuated state, peripheral inoculations of VSV-CT9-M51 targeted and killed human glioblastoma implanted into the mouse brain. Importantly, we show here that intranasal or intramuscular immunization prevents the lethal effects of subsequent VSV-G/GFP, VSV-CT1, and VSV-CT9-M51 injections into the brain. These results indicate that attenuated recombinant viruses show reduced neurovirulence and that peripheral immunization blocks the lethal actions of all VSVs tested.

* Corresponding author. Mailing address: Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-5823. Fax: (203) 737-2159. E-mail: anthony.vandenpol{at}yale.edu

{triangledown} Published ahead of print on 2 September 2009.

Journal of Virology, November 2009, p. 11540-11549, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.02558-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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