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Journal of Virology, October 2005, p. 12989-12998, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12989-12998.2005

Analysis of a Foot-and-Mouth Disease Virus Type A₂₄ Isolate Containing an SGD Receptor Recognition Site In Vitro and Its Pathogenesis in Cattle

Elizabeth Rieder,^* Tina Henry, Hernando Duque, and Barry Baxt

Foreign Animal Disease Research Unit, United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, New York 11944

Received 11 January 2005/ Accepted 6 July 2005

Foot-and-mouth disease virus (FMDV) initiates infection by binding to integrin receptors via an Arg-Gly-Asp (RGD) sequence found in the G-H loop of the structural protein VP1. Following serial passages of a type A₂₄ Cruzeiro virus (A₂₄Cru) in bovine, via tongue inoculation, a virus was generated which contained an SGD sequence in the cell receptor-binding site and expressed a turbid plaque phenotype in BHK-21 cells. Propagation of this virus in these cells resulted in the rapid selection of viruses that grew to higher titers, produced clear plaques, and now contained an RGD sequence in place of the original SGD. To study the role of the SGD sequence in FMDV receptor recognition and bovine virulence, we assembled an infectious cDNA clone of an RGD-containing A₂₄Cru and derived mutant clones containing either SGD with a single nucleotide substitution in the R₁₄₄ codon or double substitutions at this position to prevent mutation of the S to an R. The SGD viruses grew poorly in BHK-21 cells and stably maintained the sequence during propagation in BHK-21 cells expressing the bovine _Vß₆ integrin (BHK3-_Vß₆), as well as in experimentally infected and contact steers. While all the SGD-containing viruses used only the bovine _Vß₆ integrin as a cellular receptor with relatively high efficiency, the revertant RGD viruses utilized either the _Vß₁ or _Vß₃ bovine integrins with higher efficiency than _Vß₆ and grew well in BHK-21 cells. Replacing the R at the –1 SGD position with either K or E showed that this residue did not contribute to integrin utilization in vitro. These results illustrate the rapid evolution of FMDV with alteration in receptor specificity and suggest that viruses with sequences other than RGD, but closely related to it, can still infect via integrin receptors and induce and transmit the disease to susceptible animals.

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* Corresponding author. Mailing address: USDA, ARS, Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944-0848. Phone: (631) 323-3177. Fax: (631) 323-3006. E-mail: erieder{at}piadc.ars.usda.gov.

Present address: Protein Sciences Corporation, 1000 Research Parkway, Meriden, CT 06450-7159.

Present address: United States Department of Agriculture, Animal Plant Health Inspection Service, Veterinary Services, Foreign Animal Disease Diagnostic Lab, Greenport, NY 11944.

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Journal of Virology, October 2005, p. 12989-12998, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12989-12998.2005

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