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Journal of Virology, February 2008, p. 1570-1580, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01673-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Integrin {alpha}Vβ3 Binds to the RGD Motif of Glycoprotein B of Kaposi's Sarcoma-Associated Herpesvirus and Functions as an RGD-Dependent Entry Receptor{triangledown}

H. Jacques Garrigues,1 Yelena E. Rubinchikova,1 C. Michael DiPersio,2 and Timothy M. Rose1*

Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington 98195,1 Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208-34792

Received 1 August 2007/ Accepted 13 November 2007

Kaposi's sarcoma-associated herpesvirus (KSHV) envelope-associated glycoprotein B (gB) is involved in the initial steps of binding to host cells during KSHV infection. gB contains an RGD motif reported to bind the integrin {alpha}3β1 during virus entry. Although the ligand specificity of {alpha}3β1 has been controversial, current literature indicates that {alpha}3β1 ligand recognition is independent of RGD. We compared {alpha}3β1 to the RGD-binding integrin, {alpha}Vβ3, for binding to envelope-associated gB and a gB(RGD) peptide. Adhesion assays demonstrated that β3-CHO cells overexpressing {alpha}Vβ3 specifically bound gB(RGD), whereas {alpha}3-CHO cells overexpressing {alpha}3β1 did not. Function-blocking antibodies to {alpha}Vβ3 inhibited the adhesion of HT1080 fibrosarcoma cells to gB(RGD), while antibodies to {alpha}3β1 did not. Using affinity-purified integrins and confocal microscopy, {alpha}Vβ3 bound to gB(RGD) and KSHV virions, demonstrating direct receptor-ligand interactions. Specific {alpha}Vβ3 antagonists, including cyclic and dicyclic RGD peptides and {alpha}Vβ3 function-blocking antibodies, inhibited KSHV infection by 70 to 80%. Keratinocytes from {alpha}3-null mice lacking {alpha}3β1 were fully competent for infection by KSHV, and reconstitution of {alpha}3β1 function by transfection with {alpha}3 cDNA reduced KSHV infectivity from 74% to 55%. Additional inhibitory effects of {alpha}3β1 on the cell surface expression of {alpha}Vβ3 and on {alpha}Vβ3-mediated adhesion of {alpha}3-CHO cells overexpressing {alpha}3β1 were detected, consistent with previous reports of transdominant inhibition of {alpha}Vβ3 function by {alpha}3β1. These observations may explain previous reports of an inhibition of KSHV infection by soluble {alpha}3β1. Our studies demonstrate that {alpha}Vβ3 is a cellular receptor mediating both the cell adhesion and entry of KSHV into target cells through binding the virion-associated gB(RGD).

* Corresponding author. Mailing address: Department of Pathobiology, Box 357238, University of Washington, Seattle, WA 98195. Phone: (206) 616-2084. Fax: (206) 543-3873. E-mail: trose{at}u.washington.edu

{triangledown} Published ahead of print on 28 November 2007.

Journal of Virology, February 2008, p. 1570-1580, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01673-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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