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Journal of Virology, November 2004, p. 11786-11797, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11786-11797.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effects on Rotavirus Cell Binding and Infection of Monomeric and Polymeric Peptides Containing {alpha}2ß1 and {alpha}xß2 Integrin Ligand Sequences

Kate L. Graham,1 Weiguang Zeng,1,2 Yoshikazu Takada,3 David C. Jackson,1,2 and Barbara S. Coulson1*

Department of Microbiology and Immunology,1 Cooperative Research Centre for Vaccine Technology, Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia,2 UC Davis Medical Center, University of California-Davis, Sacramento, California3

Received 27 April 2004/ Accepted 28 June 2004

Integrin-using rotaviruses bind MA104 cell surface {alpha}2ß1 integrin via the Asp-Gly-Glu (DGE) sequence in virus spike protein VP4 and interact with {alpha}xß2 integrin during cell entry through outer capsid protein VP7. Infection is inhibited by the {alpha}2ß1 ligand Asp-Gly-Glu-Ala (DGEA) and the {alpha}xß2 ligand Gly-Pro-Arg-Pro (GPRP), and virus-{alpha}2ß1 binding is increased by {alpha}2ß1 activation. In this study, we analyzed the effects of monomers and polymers containing DGEA-, GPRP-, and DGEA-related peptides on rotavirus binding and infection in intestinal (Caco-2) and kidney (MA104) cells and virus binding to recombinant {alpha}2ß1. Blockade of rotavirus-cell binding and infection by peptides and anti-{alpha}2 antibody showed that Caco-2 cell entry is dependent on virus binding to {alpha}2ß1 and interaction with {alpha}xß2. At up to 0.5 mM, monomeric DGEA and DGAA inhibited binding to {alpha}2ß1 and infection. At higher concentrations, DGEA and DGAA showed a reduced ability to inhibit virus-cell binding and infection that depended on virus binding to {alpha}2ß1 but occurred without alteration in cell surface expression of {alpha}2, ß2, or {alpha}vß3 integrin. This loss of DGEA activity was abolished by genistein treatment and so was dependent on tyrosine kinase signaling. It is proposed that this signaling activated existing cell surface {alpha}2ß1 to increase virus-cell attachment and entry. Polymeric peptides containing DGEA and GPRP or GPRP only were inhibitory to SA11 infection at approximately 10-fold lower concentrations than peptide monomers. As polymerization can improve peptide inhibition of virus-receptor interactions, this approach could be useful in the development of inhibitors of receptor recognition by other viruses.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Gate 11, Royal Parade, The University of Melbourne, Melbourne, Victoria 3010, Australia. Phone: 61 3 8344 8823. Fax: 61 3 9347 1540. E-mail: barbarac{at}unimelb.edu.au.

Journal of Virology, November 2004, p. 11786-11797, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11786-11797.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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