Ay Selen, Burlaud-Gaillard Julien, Gazi Anastasia, Tatirovsky Yevgeniy, Cuche Celine, Diana Jean-Sebastien, Scoca Viviana, Di Santo James P, Roingeard Philippe, Mammano Fabrizio, Di Nunzio Francesca
Institut Pasteur, Advanced Molecular Virology Unit, Department of Virology, Université Paris Cité, 75015, Paris, France.
Inserm U1259 MAVIVHe, Université de Tours and CHRU de Tours, Tours, France.
EMBO J. 2025 Jan;44(1):166-199. doi: 10.1038/s44318-024-00316-w. Epub 2024 Dec 2.
Entry of viral capsids into the nucleus induces the formation of biomolecular condensates called HIV-1 membraneless organelles (HIV-1-MLOs). Several questions remain about their persistence, in vivo formation, composition, and function. Our study reveals that HIV-1-MLOs persisted for several weeks in infected cells, and their abundance correlated with viral infectivity. Using an appropriate animal model, we show that HIV-1-MLOs were formed in vivo during acute infection. To explore the viral structures present within these biomolecular condensates, we used a combination of double immunogold labeling, electron microscopy and tomography, and unveiled a diverse array of viral core structures. Our functional analyses showed that HIV-1-MLOs remained stable during treatment with a reverse transcriptase inhibitor, maintaining the virus in a dormant state. Drug withdrawal restored reverse transcription, promoting efficient virus replication akin to that observed in latently infected patients on antiretroviral therapy. However, when HIV-1 MLOs were deliberately disassembled by pharmacological treatment, we observed a complete loss of viral infectivity. Our findings show that HIV-1 MLOs shield the final reverse transcription product from host immune detection.
病毒衣壳进入细胞核会诱导形成称为HIV-1无膜细胞器（HIV-1-MLOs）的生物分子凝聚物。关于它们的持久性、体内形成、组成和功能仍存在几个问题。我们的研究表明，HIV-1-MLOs在受感染细胞中持续存在数周，其丰度与病毒感染性相关。使用合适的动物模型，我们表明HIV-1-MLOs在急性感染期间在体内形成。为了探索这些生物分子凝聚物中存在的病毒结构，我们结合了双重免疫金标记、电子显微镜和断层扫描，并揭示了各种各样的病毒核心结构。我们的功能分析表明，HIV-1-MLOs在用逆转录酶抑制剂治疗期间保持稳定，使病毒处于休眠状态。停药恢复了逆转录，促进了高效的病毒复制，类似于在接受抗逆转录病毒治疗的潜伏感染患者中观察到的情况。然而，当通过药物治疗故意拆解HIV-1 MLOs时，我们观察到病毒感染性完全丧失。我们的研究结果表明，HIV-1 MLOs保护最终的逆转录产物免受宿主免疫检测。
