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Journal of Virology, September 1998, p. 7091-7098, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Functional Region IV of Glycoprotein D from Herpes Simplex Virus Modulates Glycoprotein Binding to the Herpesvirus Entry Mediator

Ann H. Rux,1,2,3,* Sharon H. Willis,1,2 Anthony V. Nicola,1,2,dagger Wangfang Hou,1,2 Charline Peng,1,2 Huan Lou,1,2 Gary H. Cohen,1,2 and Roselyn J. Eisenberg1,2,3

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

Received 26 March 1998/Accepted 3 June 1998

Glycoprotein D (gD) of herpes simplex virus (HSV) is essential for virus entry and has four functional regions (I to IV) important for this process. We previously showed that a truncated form of a functional region IV variant, gD1(Delta 290-299t), had an enhanced ability to block virus entry and to bind to the herpesvirus entry mediator (HveAt; formerly HVEMt), a cellular receptor for HSV. To explore this phenotype further, we examined other forms of gD, especially ones with mutations in region IV. Variant proteins with deletions of amino acids between 277 and 300 (region IV), as well as truncated forms lacking C-terminal residues up to amino acid 275 of gD, were able to block HSV entry into Vero cells 1 to 2 logs better than wild-type gD1(306t). In contrast, gD truncated at residue 234 did not block virus entry into Vero cells. Using optical biosensor technology, we recently showed that gD1(Delta 290-299t) had a 100-fold-higher affinity for HveAt than gD1(306t) (3.3 × 10-8 M versus 3.2 × 10-6 M). Here we found that the affinities of other region IV variants for HveAt were similar to that of gD1(Delta 290-299t). Thus, the affinity data follow the same hierarchy as the blocking data. In each case, the higher affinity was due primarily to a faster kon rather than to a slower koff. Therefore, once the gDt-HveAt complex formed, its stability was unaffected by mutations in or near region IV. gD truncated at residue 234 bound to HveAt with a lower affinity (2.0 × 10-5 M) than did gD1(306t) due to a more rapid koff. These data suggest that residues between 234 and 275 are important for maintaining stability of the gDt-HveAt complex and that functional region IV is important for modulating the binding of gD to HveA. The binding properties of any gD1(234t)-receptor complex could account for the inability of this form of gDt to block HSV infection.

* Corresponding author. Mailing address: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, 4010 Locust St., Philadelphia, PA 19104-6002. Phone: (215) 898-6553. Fax: (215) 898-8385. E-mail: ahrux{at}biochem.dental.upenn.edu.

dagger Present address: Institute for Biochemistry, Swiss Federal Institute of Technology, 8092 Zurich, Switzerland.

Journal of Virology, September 1998, p. 7091-7098, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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