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Journal of Virology, February 2003, p. 2709-2716, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2709-2716.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Amino Acid Substitutions in VP2 Residues Contacting Sialic Acid in Low-Neurovirulence BeAn Virus Dramatically Reduce Viral Binding and Spread of Infection

A. S. Manoj Kumar,1,2 Patricia Kallio,1 Ming Luo,3 and Howard L. Lipton1,2,4*

Departments of Neurology,1 Microbiology-Immunology,4 Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston-Chicago, and Evanston Hospital, Evanston, Illinois,2 Center For Macromolecular Crystallography, The University of Alabama at Birmingham, Birmingham, Alabama3

Received 19 August 2002/ Accepted 14 November 2002

Theiler's murine encephalomyelitis viruses (TMEV) consist of two groups, the high- and low-neurovirulence groups, based on lethality in intracerebrally inoculated mice. Low-neurovirulence TMEV result in a persistent central nervous system infection in mice, leading to an inflammatory demyelinating pathology and disease. Low- but not high-neurovirulence strains use sialic acid as an attachment factor. The recent resolution of the crystal structure of the low-neurovirulence DA virus in complex with the sialic acid mimic sialyllactose demonstrated that four capsid residues make contact with sialic acid through noncovalent hydrogen bonds. To systematically test the importance of these sialic acid-binding residues in viral entry and infection, we mutated three VP2 puff B amino acids proposed to make contact with sialic acid and analyzed the consequences of each amino acid substitution on viral entry and spread. The fourth residue is in the VP3-VP1 cleavage dipeptide and could not be mutated. Our data suggest that residues Q2161 and G2174 are directly involved in BeAn virus attachment to sialic acid and that substitutions of these two residues result in the loss of or reduced viral binding and hemagglutination and in the inability to spread among BHK-21 cells. In addition, a gain of function-revertant virus was recovered with the Q2161A mutation after prolonged passage in cells.

* Department of Neurology, Evanston Hospital, 2650 Ridge Ave., Evanston, IL 60201. Phone: (847) 570-2168. Fax: (847) 570-1568. E-mail: hllipton{at}merle.acns.nwu.edu.

Journal of Virology, February 2003, p. 2709-2716, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2709-2716.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fan, J., Son, K.-N., Arslan, S. Y., Liang, Z., Lipton, H. L. (2009). Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells. J. Virol. 83: 6546-6553 [Abstract] [Full Text]  
  • Chiu, C. Y., Greninger, A. L., Kanada, K., Kwok, T., Fischer, K. F., Runckel, C., Louie, J. K., Glaser, C. A., Yagi, S., Schnurr, D. P., Haggerty, T. D., Parsonnet, J., Ganem, D., DeRisi, J. L. (2008). Identification of cardioviruses related to Theiler's murine encephalomyelitis virus in human infections. Proc. Natl. Acad. Sci. USA 105: 14124-14129 [Abstract] [Full Text]  
  • Kumar, A. S. M., Reddi, H. V., Kung, A. Y., Dal Canto, M., Lipton, H. L. (2004). Virus Persistence in an Animal Model of Multiple Sclerosis Requires Virion Attachment to Sialic Acid Coreceptors. J. Virol. 78: 8860-8867 [Abstract] [Full Text]  


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