Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence

David A. Stein, Stuart T. Perry, Michael D. Buck, Christopher S. Oehmen, Matthew A. Fischer, Elizabeth Poore, Jessica L. Smith, Alissa M. Lancaster, Alec Hirsch, Mark Slifka, Jay Nelson, Sujan Shresta, Klaus Frueh

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The dengue viruses (DENVs) exist as numerous genetic strains that are grouped into four antigenically distinct serotypes. DENV strains from each serotype can cause severe disease and threaten public health in tropical and subtropical regions worldwide. No licensed antiviral agent to treat DENV infections is currently available, and there is an acute need for the development of novel therapeutics. We found that a synthetic small interfering RNA (siRNA) (DC-3) targeting the highly conserved 5' cyclization sequence (5'CS) region of the DENV genome reduced, by more than 100-fold, the titers of representative strains from each DENV serotype in vitro. To determine if DC-3 siRNA could inhibit DENV in vivo, an "in vivo-ready" version of DC-3 was synthesized and tested against DENV-2 by using a mouse model of antibody-dependent enhancement of infection (ADE)-induced disease. Compared with the rapid weight loss and 5-day average survival time of the control groups, mice receiving the DC-3 siRNA had an average survival time of 15 days and showed little weight loss for approximately 12 days. DC-3-treated mice also contained significantly less virus than control groups in several tissues at various time points postinfection. These results suggest that exogenously introduced siRNA combined with the endogenous RNA interference processing machinery has the capacity to prevent severe dengue disease. Overall, the data indicate that DC-3 siRNA represents a useful research reagent and has potential as a novel approach to therapeutic intervention against the genetically diverse dengue viruses.

Original languageEnglish (US)
Pages (from-to)10154-10166
Number of pages13
JournalJournal of Virology
Volume85
Issue number19
DOIs
StatePublished - Oct 2011

Fingerprint

Dengue virus
Dengue Virus
conserved sequences
Conserved Sequence
Virus Diseases
small interfering RNA
Small Interfering RNA
cell culture
Cell Culture Techniques
mice
infection
serotypes
Weight Loss
Antibody-Dependent Enhancement
weight loss
antiviral agents
Severe Dengue
therapeutics
Control Groups
dengue

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. / Stein, David A.; Perry, Stuart T.; Buck, Michael D.; Oehmen, Christopher S.; Fischer, Matthew A.; Poore, Elizabeth; Smith, Jessica L.; Lancaster, Alissa M.; Hirsch, Alec; Slifka, Mark; Nelson, Jay; Shresta, Sujan; Frueh, Klaus.

In: Journal of Virology, Vol. 85, No. 19, 10.2011, p. 10154-10166.

Research output: Contribution to journalArticle

Stein, David A. ; Perry, Stuart T. ; Buck, Michael D. ; Oehmen, Christopher S. ; Fischer, Matthew A. ; Poore, Elizabeth ; Smith, Jessica L. ; Lancaster, Alissa M. ; Hirsch, Alec ; Slifka, Mark ; Nelson, Jay ; Shresta, Sujan ; Frueh, Klaus. / Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. In: Journal of Virology. 2011 ; Vol. 85, No. 19. pp. 10154-10166.
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