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Journal of Virology, October 2003, p. 10260-10269, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10260-10269.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Enhanced Virulence Mediated by the Murine Coronavirus, Mouse Hepatitis Virus Strain JHM, Is Associated with a Glycine at Residue 310 of the Spike Glycoprotein

Evelena Ontiveros,1 Taeg S. Kim,1 Thomas M. Gallagher,2 and Stanley Perlman1,3*

Interdisciplinary Program in Immunology,1 Departments of Pediatrics and Microbiology, University of Iowa, Iowa City, Iowa 52242,3 Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, Illinois 601532

Received 14 April 2003/ Accepted 7 July 2003

The coronavirus, mouse hepatitis virus strain JHM, causes acute and chronic neurological diseases in rodents. Here we demonstrate that two closely related virus variants, both of which cause acute encephalitis in susceptible strains of mice, cause markedly different diseases if mice are protected with a suboptimal amount of an anti-JHM neutralizing antibody. One strain, JHM.SD, caused acute encephalitis, while infection with JHM.IA resulted in no acute disease. Using recombinant virus technology, we found that the differences between the two viruses mapped to the spike (S) glycoprotein and that the two S proteins differed at four amino acids. By engineering viruses that differed by only one amino acid, we identified a serine-to-glycine change at position 310 of the S protein (S310G) that recapitulated the more neurovirulent phenotype. The increased neurovirulence mediated by the virus encoding glycine at position S310 was not associated with a different tropism within the central nervous system (CNS) but was associated with increased lateral spread in the CNS, leading to significantly higher brain viral titers. In vitro studies revealed that S310G was associated with decreased S1-S2 stability and with enhanced ability to mediate infection of cells lacking the primary receptor for JHM ("receptor-independent spread"). These enhanced fusogenic properties of viruses encoding a glycine at position 310 of the S protein may contribute to spread within the CNS, a tissue in which expression of conventional JHM receptors is low.

* Corresponding author. Mailing address: Department of Pediatrics, College of Medicine, The University of Iowa, 2042 Medical Laboratories, Iowa City, IA 52242. Phone: (319) 335-8549. Fax: (319) 335-8991. E-mail: Stanley-Perlman{at}uiowa.edu.

Journal of Virology, October 2003, p. 10260-10269, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10260-10269.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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