Abstract
How persistent viral infections are established and maintained is widely debated and remains poorly understood. We found here that the persistence of RNA viruses in Drosophila melanogaster was achieved through the combined action of cellular reverse-transcriptase activity and the RNA-mediated interference (RNAi) pathway. Fragments of diverse RNA viruses were reverse-transcribed early during infection, which resulted in DNA forms embedded in retrotransposon sequences. Those virus-retrotransposon DNA chimeras produced transcripts processed by the RNAi machinery, which in turn inhibited viral replication. Conversely, inhibition of reverse transcription hindered the appearance of chimeric DNA and prevented persistence. Our results identify a cooperative function for retrotransposons and antiviral RNAi in the control of lethal acute infection for the establishment of viral persistence.
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Acknowledgements
We thank members of the Saleh, Antoniewski and Vignuzzi laboratories for discussions and technical support; M. Vignuzzi, J. Chandler and R. van Rij for critical reading of the manuscript; A. Schneemann (The Scripps Research Institute) for antibody to FHV; P. Vargas for assistance with flow cytometry; and A. Pelisson for advice on retrotransposition. Supported by the French Agence Nationale de la Recherche (ANR-09-JCJC-0045-01 to M.-C.S.), the European Research Council (FP7/2007-2013 ERC 242703 to M.-C.S. and ERC 243312 to G.C.), Institut National de la Santé et de la Recherche Médicale and the Institut National du Cancer (G.C.), the French Ministry of Research (C.M.), La Fondation ARC pour la Recherche sur le Cancer (C.M.) and the AXA Research Fund (J.A.M.).
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B.G. and M.-C.S. designed the experiments, discussed the interpretation of the results and wrote the manuscript; G.C. participated in interpreting the data and writing the manuscript; B.G., N.V., J.A.M. and V.G. did research; H.B. generated the genomic DNA and the small-RNA libraries; N.V. and L.F. contributed to the bioinformatics analysis; and C.M., J.V.-O. and G.C. did the in vitro analysis of the reverse-transcriptase activity and AZT inhibition.
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Goic, B., Vodovar, N., Mondotte, J. et al. RNA-mediated interference and reverse transcription control the persistence of RNA viruses in the insect model Drosophila. Nat Immunol 14, 396–403 (2013). https://doi.org/10.1038/ni.2542
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DOI: https://doi.org/10.1038/ni.2542
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