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J Virol, May 1998, p. 3587-3594, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Foot-and-Mouth Disease Virus Virulent for Cattle Utilizes the Integrin alpha vbeta 3 as Its Receptor

Sherry Neff,1 Daniel Sá-Carvalho,1,dagger Elizabeth Rieder,1,Dagger Peter W. Mason,1 Scott D. Blystone,2 Eric J. Brown,2 and Barry Baxt1,*

Plum Island Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Greenport, New York 11944,1 and Washington University School of Medicine, St. Louis, Missouri 631102

Received 14 November 1997/Accepted 23 January 1998

Adsorption and plaque formation of foot-and-mouth disease virus (FMDV) serotype A12 are inhibited by antibodies to the integrin alpha vbeta 3 (A. Berinstein et al., J. Virol. 69:2664-2666, 1995). A human cell line, K562, which does not normally express alpha vbeta 3 cannot replicate this serotype unless cells are transfected with cDNAs encoding this integrin (K562-alpha vbeta 3 cells). In contrast, we found that a tissue culture-propagated FMDV, type O1BFS, was able to replicate in nontransfected K562 cells, and replication was not inhibited by antibodies to the endogenously expressed integrin alpha 5beta 1. A recent report indicating that cell surface heparan sulfate (HS) was required for efficient infection of type O1 (T. Jackson et al., J. Virol. 70:5282-5287, 1996) led us to examine the role of HS and alpha vbeta 3 in FMDV infection. We transfected normal CHO cells, which express HS but not alpha vbeta 3, and two HS-deficient CHO cell lines with cDNAs encoding human alpha vbeta 3, producing a panel of cells that expressed one or both receptors. In these cells, type A12 replication was dependent on expression of alpha vbeta 3, whereas type O1BFS replicated to high titer in normal CHO cells but could not replicate in HS-deficient cells even when they expressed alpha vbeta 3. We have also analyzed two genetically engineered variants of type O1Campos, vCRM4, which has greatly reduced virulence in cattle and can bind to heparin-Sepharose columns, and vCRM8, which is highly virulent in cattle and cannot bind to heparin-Sepharose. vCRM4 replicated in wild-type K562 cells and normal, nontransfected CHO (HS+ alpha vbeta 3-) cells, whereas vCRM8 replicated only in K562 and CHO cells transfected with alpha vbeta 3 cDNAs. A similar result was also obtained in assays using a vCRM4 virus with an engineered RGDright-arrowKGE mutation. These results indicate that virulent FMDV utilizes the alpha vbeta 3 integrin as a primary receptor for infection and that adaptation of type O1 virus to cell culture results in the ability of the virus to utilize HS as a receptor and a concomitant loss of virulence.

* Corresponding author. Mailing address: USDA, ARS, Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944-0848. Phone: (516) 323-2500. Fax: (516) 323-2507. E-mail: bbaxt{at}asrr.arsusda.gov.

dagger Present address: Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Dagger Present address: Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, NY 11794.

J Virol, May 1998, p. 3587-3594, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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