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Journal of Virology, November 2004, p. 12320-12332, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12320-12332.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Postentry Neutralization of Adenovirus Type 5 by an Antihexon Antibody

Robin Varghese,1 Yeshi Mikyas,2 Phoebe L. Stewart,2,3 and Robert Ralston1*

Canji, Inc., San Diego,1 Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California,2 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee3

Received 25 March 2004/ Accepted 6 July 2004

Antibodies against hexon, the major coat protein of adenovirus (Ad), are an important component of the neutralizing activity in serum from naturally infected humans and experimentally infected animals. The mechanisms by which antihexon antibodies neutralize the virus have not been defined. As a model system, murine monoclonal antibodies raised against Ad type 5 (Ad5) were screened for antihexon binding and neutralization activity; one monoclonal antibody, designated 9C12, was selected for further characterization. The minimum ratio of 9C12 to Ad5 required for neutralization was 240 antibody molecules per virus particle, or 1 antibody per hexon trimer. Analysis of antibody-virus complexes by dynamic light scattering and negative-stain electron microscopy (EM) showed that the virus particles were coated with electron-dense material but not aggregated at neutralizing ratios. Cryo-EM image reconstruction of the antibody-virus complex showed that the surface of the virus particle was covered by a meshwork of 9C12 antibody density, consistent with bivalent binding at multiple sites. Confocal analysis revealed that viral attachment, cell entry, and intracellular transport to the nuclear periphery still occur in the presence of neutralizing levels of 9C12. A model is presented for neutralization of Ad by an antihexon antibody in which the hexon capsid is cross-linked by antibodies, thus preventing virus uncoating and nuclear entry of viral DNA.

* Corresonding author. Mailing address: Canji, Inc., 3525 John Hopkins Ct., San Diego, CA 92121. Phone: (858) 646-5958. Fax: (858) 597-0237. E-mail: robert.ralston{at}spcorp.com.

Journal of Virology, November 2004, p. 12320-12332, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12320-12332.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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