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Attenuation of Sindbis virus neurovirulence by using defined mutations in nontranslated regions of the genome RNA

Kuhn, Richard J. and Griffin, Diane E. and Zhang, Hong and Niesters, Hubert G. M. and Strauss, James H. (1992) Attenuation of Sindbis virus neurovirulence by using defined mutations in nontranslated regions of the genome RNA. Journal of Virology, 66 (12). pp. 7121-7127. ISSN 0022-538X. PMCID PMC240395.

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We examined a panel of Sindbis virus mutants containing defined mutations in the 5' nontranslated region of the genome RNA, in the 3' nontranslated region, or in both for their growth in cultured cells and virulence in newborn mice. In cultured cells, these viruses all had defects in RNA synthesis and displayed a wide range of growth rates. The growth properties of the mutants were often very different in mouse cells from those in chicken cells or in mosquito cells. We hypothesize that host factors, presumably proteins, interact with these nontranslated regions to promote viral replication and that the mammalian protein and the chicken or mosquito protein are sufficiently divergent that alterations in the viral RNA sequence can affect the interactions with these different host proteins in different ways. Some of the mutants were temperature sensitive for plaque formation, whereas one mutant was slightly cold sensitive in its growth in chicken cells. Upon inoculation into mice, viruses that grew well in cultured mouse cells retained their virulence, but mice that succumbed usually had extended survival times. One virulent mutant that grew slightly less well in cultured mouse cells than did the parental virus produced eight times as much virus in mouse brain following intracerebral inoculation, suggesting that changes in these regulatory regions may have tissue-specific as well as host-specific effects. Viruses that were severely crippled in their growth in mouse cells in culture were usually, but not always, attenuated in their virulence. In particular, temperature sensitivity was correlated with attenuation. The effect of two mutations was found to be cumulative, and double mutants that contained mutations in both the 5' and 3' nontranslated regions were more attenuated than was either single mutant. Three of four double mutants tested were severely crippled for virus production in cultured cells and were avirulent for mice, even when inoculated intracerebrally.

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Additional Information:Copyright © 1992 by the American Society for Microbiology. Received 26 June 1992/Accepted 2 September 1992 We thank Ellen Strauss for stimulating discussions and critical reading of the manuscript and Marcia Lyons for technical assistance. This work was supported by grants DMB-9104054 from the National Science Foundation and Al 10793 from the National Institutes of Health to J.H.S. and by grant NS 18596 from the National Institutes of Health to D.E.G. R.J.K. was a recipient of Public Health Service Individual National Research Service Award AI 07869 from the National Institutes of Health. H.G.M.N. was supported in part by a fellowship grant from the Niels Stensen Foundation, a Gosney fellowship from CIT, and a travel grant from The Netherlands Organization for the Advancement of Pure Research.
Funding AgencyGrant Number
NIHAl 10793
NIHNS 18596
NIHAI 07869
Niels Stensen Foundation (NSS)UNSPECIFIED
Caltech Gosney FellowshipUNSPECIFIED
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)UNSPECIFIED
Issue or Number:12
PubMed Central ID:PMC240395
Record Number:CaltechAUTHORS:KUHjvir92
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6348
Deposited By: Archive Administrator
Deposited On:04 Dec 2006
Last Modified:02 Oct 2019 23:31

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