2. Academic Validation
  3. Genomic surveillance reveals a dengue 2 virus epidemic lineage with a marked decrease in sensitivity to Mosnodenvir

Genomic surveillance reveals a dengue 2 virus epidemic lineage with a marked decrease in sensitivity to Mosnodenvir

  • Nat Commun. 2024 Oct 9;15(1):8667. doi: 10.1038/s41467-024-52819-z.
Hawa Sophia Bouzidi # 1,  Selin Sen # 1,  Géraldine Piorkowski 1,  Laura Pezzi 1 2,  Nazli Ayhan 1 2,  Albin Fontaine 1 3,  Thomas Canivez 1 2,  Manon Geulen 1 2,  Rayane Amaral 1,  Gilda Grard 1 2,  Guillaume André Durand 1 2,  Xavier de Lamballerie 1 2,  Franck Touret 4,  Raphaëlle Klitting 5 6
Affiliations

Affiliations

  • 1 Unité des Virus Émergents (Aix-Marseille Université, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France.
  • 2 Centre National de Référence des Arbovirus, Inserm-IRBA, Marseille, France.
  • 3 Institut de Recherche Biomédicale des Armées (IRBA), Unité de virologie, Marseille, France.
  • 4 Unité des Virus Émergents (Aix-Marseille Université, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France. franck.touret@ird.fr.
  • 5 Unité des Virus Émergents (Aix-Marseille Université, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France. raphaelle.klitting@inserm.fr.
  • 6 Centre National de Référence des Arbovirus, Inserm-IRBA, Marseille, France. raphaelle.klitting@inserm.fr.
  • # Contributed equally.
PMID: 39384752 DOI: 10.1038/s41467-024-52819-z
Abstract

Dengue fever is the most important arbovirosis for public health, with more than 5 million cases worldwide in 2023. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. Here, by analyzing Dengue virus (DENV) genomes from the 2023-2024 epidemic in the French Caribbean Islands, we show that they all exhibit mutation NS4B:V91A, previously associated with a marked decrease in sensitivity to mosnodenvir in vitro. Using Antiviral activity tests on four clinical and reverse-genetic strains, we confirm a marked decrease in mosnodenvir sensitivity for DENV-2 ( > 1000 fold). Finally, combining phylogenetic analysis and experimental testing for resistance, we find that virus lineages with low sensitivity to mosnodenvir due to the V91A mutation likely emerged multiple times over the last 30 years in DENV-2 and DENV-3. These results call for increased genomic surveillance, in particular to track lineages with resistance mutations. These efforts should allow to better assess the activity profile of DENV treatments in development against circulating strains.

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