Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes

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dc.contributor.authorLevi, Laura I.en
dc.contributor.authorRezelj, Veronica V.en
dc.contributor.authorHenrion-Lacritick, Annabelleen
dc.contributor.authorErazo, Dianaen
dc.contributor.authorBoussier, Jeremyen
dc.contributor.authorVallet, Thomasen
dc.contributor.authorBernhauerova, Veronikaen
dc.contributor.authorSuzuki, Yasutsuguen
dc.contributor.authorCarrau, Luciaen
dc.contributor.authorWeger-Lucarelli, Jamesen
dc.contributor.authorSaleh, Maria-Carlaen
dc.contributor.authorVignuzzi, Marcoen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-05-25T13:07:30Zen
dc.date.available2021-05-25T13:07:30Zen
dc.date.issued2021-02en
dc.description.abstractDefective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo. Author summary Defective viral genomes (DVGs) are produced during virus replication. On their own they cannot replicate, but some of them can compete with wild-type virus for viral and/or cellular resources. For chikungunya virus, interference by DVGs has not been described. Here, we use a new approach based on experimental evolution and computational analysis to characterize all DVGs generated in a virus population and identify those with the highest antiviral potential. We confirm their antiviral activity in both mammalian and mosquito host environments and show that some can broadly interfere with other strains or related alphaviruses. Finally, we show that DVGs can inhibit virus dissemination in mosquitoes.en
dc.description.notesThis work was funded by the DARPA INTERCEPT program managed by Dr. Jim Gimlett, Dr. Brad Ringeisen and Dr. Seth Cohen, and administered though DARPA Cooperative Agreement #HR0011-17-2-0023 to M.V. and M-C. S. (the content of the information does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred). This work was also funded by the Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (grant ANR-10LABX-62-IBEID) to M.V. and M-C.S., and the Equipe FRM grant #EQU201903007777 from the French Foundation for Medical Research to M.V. L. I.L. was funded by a doctoral fellowship from France's defence procurement agency (DGA). None of the funders indicated above had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.description.sponsorshipDARPA INTERCEPT program [HR0011-17-2-0023]; Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" [ANR-10LABX-62-IBEID]; Equipe FRM grant from the French Foundation for Medical Research [EQU201903007777]; France's defence procurement agency (DGA)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1009110en
dc.identifier.eissn1553-7374en
dc.identifier.issn1553-7366en
dc.identifier.issue2en
dc.identifier.othere1009110en
dc.identifier.pmid33556143en
dc.identifier.urihttp://hdl.handle.net/10919/103488en
dc.identifier.volume17en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleDefective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoesen
dc.title.serialPlos Pathogensen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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