{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:06:57Z","timestamp":1792606017182,"version":"4.5.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"15","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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\u2032-triphosphate (5\u2032ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5\u2032ppp 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\u2032pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5\u2032pppRNA structures, RIG-I aptamers, or poly(I\u00b7C). 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\n            <jats:italic>in vitro<\/jats:italic>\n            . 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\n            <jats:italic>in vivo<\/jats:italic>\n            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\u2032pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5\u2032pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.\n          <\/jats:p>","DOI":"10.1128\/jvi.00845-15","type":"journal-article","created":{"date-parts":[[2015,5,28]],"date-time":"2015-05-28T12:53:51Z","timestamp":1432817631000},"page":"8011-8025","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":85,"title":["Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists"],"prefix":"10.1128","volume":"89","author":[{"given":"Cindy","family":"Chiang","sequence":"first","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Beljanski","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Yin","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Olagnier","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"},{"name":"Lady Davis Institute\u2014Jewish General Hospital, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fethia","family":"Ben Yebdri","sequence":"additional","affiliation":[{"name":"Lady Davis Institute\u2014Jewish General Hospital, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Steel","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Line","family":"Goulet","sequence":"additional","affiliation":[{"name":"Lady Davis Institute\u2014Jewish General Hospital, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor R.","family":"DeFilippis","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute\u2014Oregon Health and Science University, Beaverton, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"Streblow","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute\u2014Oregon Health and Science University, Beaverton, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias K.","family":"Haddad","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydie","family":"Trautmann","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted","family":"Ross","sequence":"additional","affiliation":[{"name":"Vaccine &amp; Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongtuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Lady Davis Institute\u2014Jewish General Hospital, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hiscott","sequence":"additional","affiliation":[{"name":"Vaccine &amp; 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