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Journal of Virology, September 2003, p. 9969-9978, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9969-9978.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Integrin-Using Rotaviruses Bind {alpha}2ß1 Integrin {alpha}2 I Domain via VP4 DGE Sequence and Recognize {alpha}Xß2 and {alpha}Vß3 by Using VP7 during Cell Entry

Kate L. Graham,1 Peter Halasz,1 Yan Tan,1 Marilyn J. Hewish,1 Yoshikazu Takada,2 Erich R. Mackow,3 Martyn K. Robinson,4 and Barbara S. Coulson1*

Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia,1 Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, California 92307,2 The Department of Medicine and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, and Northport VAMC, Northport, New York 11794,3 Celltech Group plc., Slough SL1 4EN, United Kingdom4

Received 8 April 2003/ Accepted 25 June 2003

Integrins {alpha}2ß1, {alpha}Xß2, and {alpha}Vß3 have been implicated in rotavirus cell attachment and entry. The virus spike protein VP4 contains the {alpha}2ß1 ligand sequence DGE at amino acid positions 308 to 310, and the outer capsid protein VP7 contains the {alpha}Xß2 ligand sequence GPR. To determine the viral proteins and sequences involved and to define the roles of {alpha}2ß1, {alpha}Xß2, and {alpha}Vß3, we analyzed the ability of rotaviruses and their reassortants to use these integrins for cell binding and infection and the effect of peptides DGEA and GPRP on these events. Many laboratory-adapted human, monkey, and bovine viruses used integrins, whereas all porcine viruses were integrin independent. The integrin-using rotavirus strains each interacted with all three integrins. Integrin usage related to VP4 serotype independently of sialic acid usage. Analysis of rotavirus reassortants and assays of virus binding and infectivity in integrin-transfected cells showed that VP4 bound {alpha}2ß1, and VP7 interacted with {alpha}Xß2 and {alpha}Vß3 at a postbinding stage. DGEA inhibited rotavirus binding to {alpha}2ß1 and infectivity, whereas GPRP binding to {alpha}Xß2 inhibited infectivity but not binding. The truncated VP5* subunit of VP4, expressed as a glutathione S-transferase fusion protein, bound the expressed {alpha}2 I domain. Alanine mutagenesis of D308 and G309 in VP5* eliminated VP5* binding to the {alpha}2 I domain. In a novel process, integrin-using viruses bind the {alpha}2 I domain of {alpha}2ß1 via DGE in VP4 and interact with {alpha}Xß2 (via GPR) and {alpha}Vß3 by using VP7 to facilitate cell entry and infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Gate II, The University of Melbourne, Melbourne, Victoria 3010, Australia. Phone: 61-38344-8823. Fax: 61-39347-1540. E-mail: barbarac{at}unimelb.edu.au.

Journal of Virology, September 2003, p. 9969-9978, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9969-9978.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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