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Journal of Virology, May 1999, p. 3951-3959, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cellular Entry of Hantaviruses Which Cause Hemorrhagic Fever with Renal Syndrome Is Mediated by beta 3 Integrins

Irina N. Gavrilovskaya,1,2 Eric J. Brown,3 Mark H. Ginsberg,4 and Erich R. Mackow1,2,5,*

Department of Medicine1 and Department of Molecular Genetics and Microbiology,2 State University of New York at Stony Brook, Stony Brook, New York 11794; Washington University School of Medicine, St. Louis Missouri 631103; Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 920374; and Northport Veterans Administration Medical Center, Northport, New York 117685

Received 17 November 1998/Accepted 27 January 1999

Hantaviruses replicate primarily in the vascular endothelium and cause two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In this report, we demonstrate that the cellular entry of HFRS-associated hantaviruses is facilitated by specific integrins expressed on platelets, endothelial cells, and macrophages. Infection of human umbilical vein endothelial cells and Vero E6 cells by the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala (PUU) is inhibited by antibodies to alpha vbeta 3 integrins and by the integrin ligand vitronectin. The cellular entry of HTN, SEO, and PUU viruses, but not the nonpathogenic Prospect Hill (PH) hantavirus (i.e., a virus with no associated human disease), was also mediated by introducting recombinant alpha IIbbeta 3 or alpha vbeta 3 integrins into beta 3-integrin-deficient CHO cells. In addition, PH infectivity was not inhibited by alpha vbeta 3-specific sera or vitronectin but was blocked by alpha 5beta 1-specific sera and the integrin ligand fibronectin. RGD tripeptides, which are required for many integrin-ligand interactions, are absent from all hantavirus G1 and G2 surface glycoproteins, and GRGDSP peptides did not inhibit hantavirus infectivity. Further, a mouse-human hybrid beta 3 integrin-specific Fab fragment, c7E3 (ReoPro), also inhibited the infectivity of HTN, SEO, and PUU as well as HPS-associated hantaviruses, Sin Nombre (SN) and New York-1 (NY-1). These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses enter cells via beta 3 integrins, which are present on the surfaces of platelets, endothelial cells, and macrophages. Since beta 3 integrins regulate vascular permeability and platelet function, these findings also correlate beta 3 integrin usage with common elements of hantavirus pathogenesis.

* Corresponding author. Mailing address: Departments of Medicine and of Molecular Genetics and Microbiology, SUNY at Stony Brook, HSC T17, Rm. 60, Stony Brook, NY 11794. Phone: (516) 444-2120. Fax: (516) 444-8886. E-mail: EMackow{at}mail.son.sunysb.edu.

Journal of Virology, May 1999, p. 3951-3959, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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