Unité des Virus Émergents (Aix-Marseille Université, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France.
Centre National de Référence des Arbovirus, Inserm-IRBA, Marseille, France.
Nat Commun. 2024 Oct 9;15(1):8667. doi: 10.1038/s41467-024-52819-z.
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.
登革热是对公共卫生最重要的虫媒病毒病，2023 年全球有超过 500 万例病例。Mosnodenvir 是第一个具有很高的泛血清型活性的抗登革病毒化合物，目前正在进行 2 期临床评估。在这里，我们通过分析 2023-2024 年法属加勒比地区流行的登革热病毒（DENV）基因组，发现它们都表现出突变 NS4B:V91A，之前与体外对 mosnodenvir 的敏感性显著降低有关。我们使用对四种临床和反向遗传株的抗病毒活性测试，证实了 mosnodenvir 对 DENV-2 的敏感性显著降低（>1000 倍）。最后，结合遗传进化分析和抗药性实验测试，我们发现由于 V91A 突变而对 mosnodenvir 敏感性降低的病毒谱系很可能在过去 30 年中在 DENV-2 和 DENV-3 中多次出现。这些结果呼吁加强基因组监测，特别是要追踪具有耐药突变的谱系。这些努力应能更好地评估针对流行株开发的登革热治疗药物的活性谱。
