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Molecular basis of Sindbis virus neurovirulence in mice

Lustig, Shlomo and Jackson, Alan C. and Hahn, Chang S. and Griffin, Diane E. and Strauss, Ellen G. and Strauss, James H. (1988) Molecular basis of Sindbis virus neurovirulence in mice. Journal of Virology, 62 (7). pp. 2329-2336. ISSN 0022-538X. http://resolver.caltech.edu/CaltechAUTHORS:LUSjvir88

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Abstract

We examined a variety of strains of Sindbis virus for the genetic changes responsible for differences in neurovirulence in mice. SV1A (a low passage of the AR339 strain of Sindbis virus), a neuroadapted Sindbis virus (NSV), and two laboratory strains of Sindbis virus (HRSP and Toto1101) were examined. NSV causes severe encephalomyelitis with hind-limb paralysis and high mortality after intracerebral inoculation in weanling mice. In contrast, SV1A causes only mild, nonfatal disease in weanling mice; however, in suckling mice, SV1A causes a fatal encephalomyelitis after either intracerebral or subcutaneous inoculation. The two laboratory strains used have a greatly reduced neurovirulence for suckling mice and are avirulent for weanling mice. The nucleotide sequences and encoded amino acid sequences of the structural glycoproteins of these four strains were compared. Hybrid genomes were constructed by replacing restriction fragments in a full-length cDNA clone of Sindbis virus, from which infectious RNA can be transcribed in vitro, with fragments from cDNA clones of the various strains. These recombinant viruses allowed us to test the importance of each amino acid difference between the various strains for neurovirulence in weanling and suckling mice. Glycoproteins E2 and E1 were of paramount importance for neurovirulence in adult mice. Recombinant viruses containing the nonstructural protein region and the capsid protein region from an avirulent strain and the E1 and E2 glycoprotein regions from NSV were virulent, although they were less virulent than NSV. Furthermore, changes in either E2 (His-55 in NSV to Gln in SV1A) or E1 (Ala-72 in NSV to Val in SV1A and Asp-313 in NSV to Gly in SV1A) reduced virulence. For virulence in suckling mice, we found that a number of changes in E2 and E1 can lead to decreased virulence and that in fact, a gradient of virulence exists.


Item Type:Article
Additional Information:Copyright © 1988 by the American Society for Microbiology. Received 1 February 1988/Accepted 16 March 1988 We thank Y. S. Hahn for participating in the rescue of some of the virus constructs, E. M. Lenches for expert technical assistance, and R. Johnston and colleagues for sharing their results before publication. This work was supported by Public Health Service grants AI 10793 and AI 20612 (to J.H.S.) and NS 18596 (to D.E.G.) from the National Institutes of Health. A.C.J. is the recipient of a postdoctoral fellowship from the Multiple Sclerosis Society of Canada.
Record Number:CaltechAUTHORS:LUSjvir88
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LUSjvir88
Alternative URL:http://jvi.asm.org/cgi/content/abstract/62/7/2329
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ID Code:2285
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:21 Mar 2006
Last Modified:26 Dec 2012 08:48

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