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Journal of Virology, April 2005, p. 4219-4228, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4219-4228.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Adult Mouse Neurovirulence Determinants of the Sindbis Virus Strain AR86

Mehul S. Suthar,1 Reed Shabman,1 Kenya Madric,1 Cassandra Lambeth,1 and Mark T. Heise1,2*

Department of Genetics,2 Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina1

Received 11 August 2004/ Accepted 12 November 2004

Sindbis virus infection of mice has provided valuable insight into viral and host factors that contribute to virus-induced neurologic disease. In an effort to further define the viral genetic elements that contribute to adult mouse neurovirulence, the neurovirulent Sindbis virus strain AR86 was compared to the closely related (22 single amino acid coding changes and the presence or absence of an 18-amino-acid sequence in nsP3 [positions 386 to 403]) but avirulent Girdwood strain. Initial studies using chimeric viruses demonstrated that genetic elements within the nonstructural and structural coding regions contributed to AR86 neurovirulence. Detailed mapping studies identified three major determinants in the nonstructural region, at nsP1 538 (Ile to Thr; avirulent to virulent), an 18-amino-acid deletion in nsP3 (positions 386 to 403), and nsP3 537 (opal to Cys; avirulent to virulent), as well as a single determinant in the structural genes at E2 243 (Leu to Ser; avirulent to virulent), which were essential for AR86 adult mouse neurovirulence. Replacing these codons in AR86 with those found in Girdwood resulted in the attenuation of AR86, while the four corresponding AR86 changes in the Girdwood genetic background increased virulence to the level of wild-type AR86. The attenuating mutations did not adversely affect viral replication in vitro, and the attenuated viruses established infection in the brain and spinal cord as efficiently as the virulent viruses. However, the virus containing the four virulence determinants grew to higher levels in the spinal cord at late times postinfection, suggesting that the virus containing the four attenuating determinants either failed to spread or was cleared more efficiently than the wild-type virus.

* Corresponding author. Mailing address: The Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, 827 Mary Ellen Jones Building, CB #7292, Chapel Hill, NC 27599. Phone: (919) 966-1492. Fax: (919) 843-6924. E-mail: heisem{at}med.unc.edu.

Journal of Virology, April 2005, p. 4219-4228, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4219-4228.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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