Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists

Cindy Chiang, Vladimir Beljanski, Kevin Yin, David Olagnier, Fethia Ben Yebdri, Courtney Steel, Marie Line Goulet, Victor De Filippis, Daniel Streblow, Elias K. Haddad, Lydie Trautmann, Ted Ross, Rongtuan Lin, John Hiscott

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Abstract

The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5'-triphosphate (5'ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5'ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5'pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5'pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5'pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses.

Original languageEnglish (US)
Pages (from-to)8011-8025
Number of pages15
JournalJournal of Virology
Volume89
Issue number15
DOIs
StatePublished - 2015

Fingerprint

retinoic acid
Tretinoin
agonists
Antiviral Agents
Orthomyxoviridae
Genes
viral load
genes
influenza
Human Influenza
RNA Virus Infections
inflammation
Uracil Nucleotides
Chikungunya virus
Oseltamivir
polyinosinic-polycytidylic acid
Dengue virus
therapeutics
Dengue Virus
uridine

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Chiang, C., Beljanski, V., Yin, K., Olagnier, D., Yebdri, F. B., Steel, C., ... Hiscott, J. (2015). Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists. Journal of Virology, 89(15), 8011-8025. https://doi.org/10.1128/JVI.00845-15

Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists. / Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin; Olagnier, David; Yebdri, Fethia Ben; Steel, Courtney; Goulet, Marie Line; De Filippis, Victor; Streblow, Daniel; Haddad, Elias K.; Trautmann, Lydie; Ross, Ted; Lin, Rongtuan; Hiscott, John.

In: Journal of Virology, Vol. 89, No. 15, 2015, p. 8011-8025.

Research output: Contribution to journalArticle

Chiang, C, Beljanski, V, Yin, K, Olagnier, D, Yebdri, FB, Steel, C, Goulet, ML, De Filippis, V, Streblow, D, Haddad, EK, Trautmann, L, Ross, T, Lin, R & Hiscott, J 2015, 'Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists', Journal of Virology, vol. 89, no. 15, pp. 8011-8025. https://doi.org/10.1128/JVI.00845-15
Chiang, Cindy ; Beljanski, Vladimir ; Yin, Kevin ; Olagnier, David ; Yebdri, Fethia Ben ; Steel, Courtney ; Goulet, Marie Line ; De Filippis, Victor ; Streblow, Daniel ; Haddad, Elias K. ; Trautmann, Lydie ; Ross, Ted ; Lin, Rongtuan ; Hiscott, John. / Sequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists. In: Journal of Virology. 2015 ; Vol. 89, No. 15. pp. 8011-8025.
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