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J Virol, May 1998, p. 3595-3601, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Monoclonal Antibodies to Distinct Sites on Herpes Simplex Virus (HSV) Glycoprotein D Block HSV Binding to HVEM

Anthony V. Nicola,1,2,dagger Manuel Ponce de Leon,1,2 Ruliang Xu,1,2,Dagger Wangfang Hou,1,2 J. Charles Whitbeck,1,2 Claude Krummenacher,1,2 Rebecca I. Montgomery,3 Patricia G. Spear,3 Roselyn J. Eisenberg,2,4,* and Gary H. Cohen1,2

Department of Microbiology1 and Center for Oral Health Research,2 School of Dental Medicine, and Department of Pathobiology, School of Veterinary Medicine,4 University of Pennsylvania, Philadelphia, Pennsylvania, and Department of Microbiology-Immunology, Northwestern University School of Medicine, Chicago, Illinois3

Received 15 December 1997/Accepted 26 January 1998

HVEM (for herpesvirus entry mediator) is a member of the tumor necrosis factor receptor superfamily and mediates entry of many strains of herpes simplex virus (HSV) into normally nonpermissive Chinese hamster ovary (CHO) cells. We used sucrose density centrifugation to demonstrate that purified HSV-1 KOS virions bind directly to a soluble, truncated form of HVEM (HVEMt) in the absence of any other cell-associated components. Therefore, HVEM mediates HSV entry by serving as a receptor for the virus. We previously showed that soluble, truncated forms of HSV glycoprotein D (gDt) bind to HVEMt in vitro. Here we show that antibodies specific for gD, but not the other entry glycoproteins gB, gC, or the gH/gL complex, completely block HSV binding to HVEM. Thus, virion gD is the principal mediator of HSV binding to HVEM. To map sites on virion gD which are necessary for its interaction with HVEM, we preincubated virions with gD-specific monoclonal antibodies (MAbs). MAbs that recognize antigenic sites Ib and VII of gD were the only MAbs which blocked the HSV-HVEM interaction. MAbs from these two groups failed to coprecipitate HVEMt in the presence of soluble gDt, whereas the other anti-gD MAbs coprecipitated HVEMt and gDt. Previous mapping data indicated that site VII includes amino acids 11 to 19 and site Ib includes 222 to 252. The current experiments indicate that these sites contain residues important for HSV binding to HVEM. Group Ib and VII MAbs also blocked HSV entry into HVEM-expressing CHO cells. These results suggest that the mechanism of neutralization by these MAbs is via interference with the interaction between gD in the virus and HVEM on the cell. Group Ia and II MAbs failed to block HSV binding to HVEM yet still neutralized HVEM-mediated entry, suggesting that these MAbs block entry at a step other than HVEM binding.

* Corresponding author. Mailing address: Center for Oral Health Research, University of Pennsylvania, 4010 Locust St., Philadelphia, PA 19104-6002. Phone: (215) 898-6552. Fax: (215) 898-8385. E-mail: roselyn{at}biochem.dental.upenn.edu.

dagger Present address: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520.

Dagger Present address: Department of Pathology, New York University Medical Center, Bellevue Hospital, New York, NY 10016.

J Virol, May 1998, p. 3595-3601, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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