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Journal of Virology, January 2001, p. 171-180, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.171-180.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Localization of the gD-Binding Region of the Human Herpes Simplex Virus Receptor, HveA

J. Charles Whitbeck,1,2,3,* Sarah A. Connolly,1,2 Sharon H. Willis,1,2 Wangfang Hou,1,2 Claude Krummenacher,1,2 Manuel Ponce de Leon,1,2 Huan Lou,1,2 Isabelle Baribaud,1,2 Roselyn J. Eisenberg,2,3 and Gary H. Cohen1,2

Department of Microbiology1 and Center for Oral Health Research,2 School of Dental Medicine, and School of Veterinary Medicine,3 University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 28 July 2000/Accepted 11 October 2000

During virus entry, herpes simplex virus (HSV) glycoprotein D (gD) binds to one of several human cellular receptors. One of these, herpesvirus entry mediator A (HveA), is a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ectodomain contains four characteristic cysteine-rich pseudorepeat (CRP) elements. We previously showed that gD binds the ectodomain of HveA expressed as a truncated, soluble protein [HveA(200t)]. To localize the gD-binding domain of HveA, we expressed three additional soluble forms of HveA consisting of the first CRP [HveA(76t)], the second CRP [HveA(77-120t)], or the first and second CRPs [HveA(120t)]. Biosensor and enzyme-linked immunosorbent assay studies showed that gD bound to HveA(120t) and HveA(200t) with the same affinity. However, gD did not bind to HveA(76t) or HveA(77-120t). Furthermore, HveA(200t) and HveA(120t), but not HveA(76t) or HveA(77-120t), blocked herpes simplex virus (HSV) entry into CHO cells expressing HveA. We also generated six monoclonal antibodies (MAbs) against HveA(200t). MAbs CW1, -2, and -4 bound linear epitopes within the second CRP, while CW7 and -8 bound linear epitopes within the third or fourth CRPs. None of these MAbs blocked the binding of gD to HveA. In contrast, MAb CW3 recognized a discontinuous epitope within the first CRP of HveA, blocked the binding of gD to HveA, and exhibited a limited ability to block virus entry into cells expressing HveA, suggesting that the first domain of HveA contains at least a portion of the gD binding site. The inability of gD to bind HveA(76t) suggests that additional amino acid residues of the gD binding site may reside within the second CRP.

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

Journal of Virology, January 2001, p. 171-180, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.171-180.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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