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Journal of Virology, April 2002, p. 3452-3460, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3452-3460.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Adenovirus Binding to the Coxsackievirus and Adenovirus Receptor or Integrins Is Not Required To Elicit Brain Inflammation but Is Necessary To Transduce Specific Neural Cell Types

Clare E. Thomas,1,{dagger} Penny Edwards,1 Thomas J. Wickham,2 Maria G. Castro,1,3* and Pedro R. Lowenstein1,3*

Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester, United Kingdom,1 GenVec, Inc., Rockville, Maryland 20852,2 Gene Therapeutics Research Institute, Los Angeles, California 900483

Received 10 September 2001/ Accepted 13 December 2001

Intracranial administration of adenovirus vectors elicits rapid, capsid-mediated dose-dependent brain inflammation. The mechanisms through which adenovirus capsids trigger inflammation in the brain remain unknown. We determined whether adenovirus interaction with the primary and secondary cell surface receptors for infection (CAR and {alpha}v integrins) was necessary to trigger acute adenovirus-mediated brain inflammation, and, furthermore, whether capsid mutations that abrogated CAR and integrin binding altered vector tropism in the brain. Vectors ablated for CAR binding, but retaining integrin binding function, transduced equivalent areas of brain compared to vectors with wild-type capsids; however, vector tropsim was dramatically altered. Vectors with wild-type capsids predominantly transduced oligodendrocytes, whereas mutation of the fiber protein to ablate CAR binding resulted in a loss of oligodendrocyte transduction and a consequent redirection of transduction to neurons and other types of glial cells. Combined mutations of fiber and penton base that ablate both CAR and integrin binding almost abolished brain transduction. Thus, doubly-ablated capsids engineered to express new ligands should allow complete vector retargeting in the central nervous system. Although transduction by the doubly-ablated vectors was reduced by greater than 95%, inflammation was not reduced compared to wild-type vectors, demonstrating that brain inflammation occurs independently of adenovirus binding and infection of cells via CAR and integrin receptors.

* Corresponding author. Mailing address: Gene Therapeutics Research Institute, Research Pavilion, Room 5090, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 423-7302. Fax: (310) 423-0225. E-mail: castromg{at}cshs.org.

* Corresponding author. Mailing address: Gene Therapeutics Research Institute, Research Pavilion, Room 5090, 8700 Beverly Blvd., Los Angeles, CA 90048. Phone: (310) 423-7330. Fax: (310) 423-7308. E-mail: lowensteinp{at}cshs.org.

{dagger} Present address: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208.

Journal of Virology, April 2002, p. 3452-3460, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3452-3460.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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