Speaker
Description
Dengue fever is the most important arbovirosis for public health, with more than 6 million cases worldwide in 2023. The virus is present in the subtropical and tropical regions of the world often in co-circulation with over arboviroses. There is currently no effective treatment commercially available. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. JNJ-1802, its scientific name, inhibits the viral complex between the non-structral protein 3 (NS3) and the non-structural protein 4B (NS4B), effectively stopping viral replication. Here, by analyzing dengue virus (DENV) genomes from the 2023-2024 DENV-2 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). Using Bayesian inference, we estimate that the period of emergence of this mutation may have shortly preceded the emergence of the French Caribbean island epidemic lineage. By 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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