Defective viral genomes as therapeutic interfering particles against flavivirus infection in mammalian and mosquito hosts

Veronica V. Rezelj, Lucía Carrau, Fernando Merwaiss, Laura I. Levi, Diana Erazo, Quang Dinh Tran, Annabelle Henrion-Lacritick, Valérie Gausson, Yasutsugu Suzuki, Djoshkun Shengjuler, Bjoern Meyer, Thomas Vallet, James Weger-Lucarelli, Veronika Bernhauerová, Avi Titievsky, Vadim Sharov, Stefano Pietropaoli, Marco A. Diaz-Salinas, Vincent Legros, Nathalie Pardigon, Giovanna Barba-Spaeth, Leonid Brodsky, Maria-Carla Saleh () and Marco Vignuzzi ()
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Veronica V. Rezelj: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Lucía Carrau: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Fernando Merwaiss: Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569
Laura I. Levi: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Diana Erazo: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Quang Dinh Tran: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Annabelle Henrion-Lacritick: Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569
Valérie Gausson: Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569
Yasutsugu Suzuki: Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569
Djoshkun Shengjuler: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Bjoern Meyer: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Thomas Vallet: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
James Weger-Lucarelli: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Veronika Bernhauerová: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569
Avi Titievsky: University of Haifa
Vadim Sharov: University of Haifa
Stefano Pietropaoli: Institut Pasteur, Unité de Virologie Structurale, Centre National de la Recherche Scientifique UMR 3569
Marco A. Diaz-Salinas: Institut Pasteur, Unité de Recherche et d’Expertise Environnement et Risques Infectieux, Groupe Arbovirus
Vincent Legros: Institut Pasteur, Unité de Virologie Structurale, Centre National de la Recherche Scientifique UMR 3569
Nathalie Pardigon: Institut Pasteur, Unité de Recherche et d’Expertise Environnement et Risques Infectieux, Groupe Arbovirus
Giovanna Barba-Spaeth: Institut Pasteur, Unité de Virologie Structurale, Centre National de la Recherche Scientifique UMR 3569
Leonid Brodsky: University of Haifa
Maria-Carla Saleh: Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la Recherche Scientifique UMR 3569
Marco Vignuzzi: Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.

Date: 2021
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DOI: 10.1038/s41467-021-22341-7

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