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Journal of Virology, June 2008, p. 5750-5760, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02673-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Sindbis Virus Conformational Changes Induced by a Neutralizing Anti-E1 Monoclonal Antibody{triangledown}

Raquel Hernandez,1* Angel Paredes,2 and Dennis T. Brown1

Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, North Carolina 27608,1 University of Texas Health Sciences Center, Houston, Texas 770302

Received 17 December 2007/ Accepted 6 April 2008

A rare Sindbis virus anti-E1 neutralizing monoclonal antibody, Sin-33, was investigated to determine the mechanism of in vitro neutralization. A cryoelectron microscopic reconstruction of Sindbis virus (SVHR) neutralized with FAb from Sin-33 (FAb-33) revealed conformational changes on the surface of the virion at a resolution of 24 Å. FAb-33 was found to bind E1 in less than 1:1 molar ratios, as shown by the absence of FAb density in the reconstruction and stoichiometric measurements using radiolabeled FAb-33, which determined that about 60 molecules of FAb-33 bound to the 240 possible sites in a single virus particle. FAb-33-neutralized virus particles became sensitive to digestion by endoproteinase Glu-C, providing further evidence of antibody-induced structural changes within the virus particle. The treatment of FAb-33-neutralized or Sin-33-neutralized SVHR with low pH did not induce the conformational rearrangements required for virus membrane-cell membrane fusion. Exposure to low pH, however, increased the amount of Sin-33 or FAb-33 that bound to the virus particles, indicating the exposure of additional epitopes. The neutralization of SVHR infection by FAb-33 or Sin-33 did not prevent the association of virus with host cells. These data are in agreement with the results of previous studies that demonstrated that specific antibodies can inactivate the infectious state of a metastable virus in vitro by the induction of conformational changes to produce an inactive structure. A model is proposed which postulates that the induction of conformational changes in the infectious state of a metastable enveloped virus may be a general mechanism of antibody inactivation of virus infectivity.

* Corresponding author. Mailing address: Department of Molecular and Structural Biochemistry, North Carolina State University, Campus Box 7622, Raleigh, NC 27695-7622. Phone: (919) 515-5765. Fax: (919) 515-2047. E-mail: raquel_hernandez{at}ncsu.edu

{triangledown} Published ahead of print on 16 April 2008.

Journal of Virology, June 2008, p. 5750-5760, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02673-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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