JVI Figure table search 04
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by White, L. J.
Right arrow Articles by Johnston, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by White, L. J.
Right arrow Articles by Johnston, R. E.

 Previous Article  |  Next Article 

Journal of Virology, April 2001, p. 3706-3718, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3706-3718.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Role of Alpha/Beta Interferon in Venezuelan Equine Encephalitis Virus Pathogenesis: Effect of an Attenuating Mutation in the 5' Untranslated Region

Laura J. White,1,* Jia-Gang Wang,2 Nancy L. Davis,1 and Robert E. Johnston1

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill,1 and Bayer Corporation, Clayton,2 North Carolina

Received 7 November 2000/Accepted 29 January 2001

Venezuelan equine encephalitis virus (VEE) is an important equine and human pathogen of the Americas. In the adult mouse model, cDNA-derived, virulent V3000 inoculated subcutaneously (s.c.) causes high-titer peripheral replication followed by neuroinvasion and lethal encephalitis. A single change (G to A) at nucleotide 3 (nt 3) of the 5' untranslated region (UTR) of the V3000 genome resulted in a virus (V3043) that was avirulent in mice. The mechanism of attenuation by the V3043 mutation was studied in vivo and in vitro. Kinetic studies of virus spread in adult mice following s.c. inoculation showed that V3043 replication was reduced in peripheral organs compared to that of V3000, titers in serum also were lower, and V3043 was cleared more rapidly from the periphery than V3000. Because clearance of V3043 from serum began 1 to 2 days prior to clearance of V3000, we examined the involvement of alpha/beta interferon (IFN-alpha /beta ) activity in VEE pathogenesis. In IFN-alpha /beta R-/- mice, the course of the wild-type disease was extremely rapid, with all animals dying within 48 h (average survival time of 30 h compared to 7.7 days in the wild-type mice). The mutant V3043 was as virulent as the wild type (100% mortality, average survival time of 30 h). Virus titers in serum, peripheral organs, and the brain were similar in V3000- and V3043-infected IFN-alpha /beta R-/- mice at all time points up until the death of the animals. Consistent with the in vivo data, the mutant virus exhibited reduced growth in vitro in several cell types except in cells that lacked a functional IFN-alpha /beta pathway. In cells derived from IFN-alpha /beta R-/- mice, the mutant virus showed no growth disadvantage compared to the wild-type virus, suggesting that IFN-alpha /beta plays a major role in the attenuation of V3043 compared to V3000. There were no differences in the induction of IFN-alpha /beta between V3000 and V3043, but the mutant virus was more sensitive than V3000 to the antiviral actions of IFN-alpha /beta in two separate in vitro assays, suggesting that the increased sensitivity to IFN-alpha /beta plays a major role in the in vivo attenuation of V3043.

* Corresponding author. Mailing address: 836 Mary Ellen Jones Bldg., CB 7290, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7290. Phone: (919) 966-4026. Fax: (919) 843-6924. E-mail: ljwhite{at}med.unc.edu.

Journal of Virology, April 2001, p. 3706-3718, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3706-3718.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. Mol. Cell. Biol. Microbiol. Mol. Biol. Rev.
Clin. Vaccine Immunol. ALL ASM JOURNALS

Copyright © 2001 by the American Society for Microbiology. All rights reserved.