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

Hawa Sophia Bouzidi1, Selin Sen1, Géraldine Piorkowski1

  • 1Unité des Virus Émergents (Aix-Marseille Université, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France.

Nature Communications
|October 9, 2024
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Summary

Dengue virus (DENV) strains in the French Caribbean show a mutation reducing sensitivity to the promising antiviral mosnodenvir. Genomic surveillance is vital to track these resistant DENV strains and ensure effective treatment development.

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Area of Science:

  • Virology
  • Public Health
  • Genomics

Background:

  • Dengue fever is a major global arbovirosis, with over 5 million cases in 2023.
  • Mosnodenvir is a novel antiviral compound showing preclinical pan-serotype activity against dengue virus (DENV).

Purpose of the Study:

  • To investigate the sensitivity of circulating DENV strains from the French Caribbean to mosnodenvir.
  • To identify genetic markers associated with reduced mosnodenvir sensitivity in DENV.

Main Methods:

  • Genomic analysis of DENV strains from the 2023-2024 epidemic in the French Caribbean.
  • Antiviral activity testing of mosnodenvir against clinical and reverse-genetic DENV strains.
  • Phylogenetic analysis to track the emergence and spread of resistant DENV lineages.

Main Results:

  • All analyzed DENV genomes from the French Caribbean exhibited the NS4B:V91A mutation.
  • This mutation was previously linked to decreased mosnodenvir sensitivity.
  • DENV-2 strains with the V91A mutation showed over 1000-fold reduced sensitivity to mosnodenvir in vitro.
  • Phylogenetic analysis indicated multiple independent emergences of mosnodenvir-resistant DENV-2 and DENV-3 lineages over the past 30 years.

Conclusions:

  • The NS4B:V91A mutation confers significant resistance to mosnodenvir in DENV.
  • Increased genomic surveillance is crucial for monitoring DENV resistance mutations.
  • This surveillance will aid in evaluating the efficacy of DENV therapeutics against circulating strains.