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Journal of Virology, March 2002, p. 2424-2433, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2424-2433.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effects of Herpes Simplex Virus on Structure and Function of Nectin-1/HveC

*** Claude Krummenacher,1,2* Isabelle Baribaud,1,2 James F. Sanzo,3,{dagger} Gary H. Cohen,1,2 and Roselyn J. Eisenberg2,4

Department of Microbiology,1 Center for Oral Health Research, School of Dental Medicine,2 Department of Bioengineering, School of Engineering and Applied Sciences,3 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191044

Received 2 October 2001/ Accepted 5 December 2001

Herpes simplex virus (HSV) entry requires the interaction between the envelope glycoprotein D (gD) and a cellular receptor such as nectin-1 (also named herpesvirus entry mediator C [HveC]) or HveA/HVEM. Nectin-1 is a cell adhesion molecule found at adherens junctions associated with the cytoplasmic actin-binding protein afadin. Nectin-1 can act as its own ligand in a homotypic interaction to bridge cells together. We used a cell aggregation assay to map an adhesive functional site on nectin-1 and identify the effects of gD binding and HSV early infection on nectin-1 function. Soluble forms of nectin-1 and anti-nectin-1 monoclonal antibodies were used to map a functional adhesive site within the first immunoglobulin-like domain (V domain) of nectin-1. This domain also contains the gD-binding site, which appeared to overlap the adhesive site. Thus, soluble forms of gD were able to prevent nectin-1-mediated cell aggregation and to disrupt cell clumps in an affinity-dependent manner. HSV also prevented nectin-1-mediated cell aggregation by occupying the receptor. Early in infection, nectin-1 was not downregulated from the cell surface. Rather, detection of nectin-1 changed gradually over a 30-min period of infection, as reflected by a decrease in the CK41 epitope and an increase in the CK35 epitope. The level of detection of virion gD on the cell surface increased within 5 min of infection in a receptor-dependent manner. These observations suggest that cell surface nectin-1 and gD may undergo conformational changes during HSV entry as part of an evolving interaction between the viral envelope and the cell plasma membrane.

* Corresponding author. Mailing address: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6002. Phone: (215) 898-6553. Fax: (215) 898-8385. E-mail: krumm{at}biochem.dental.upenn.edu.

{dagger} Present address: AviGenics, Inc., Athens, Ga.

Journal of Virology, March 2002, p. 2424-2433, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2424-2433.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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