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Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The “block and lock” approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the “block and lock” strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the “block and lock” strategy in the pursuit of an HIV-1 cure.

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Fig. 1: Screening of an FDA-approved compound library identified ripretinib as an LPA candidate.
Fig. 2: Ripretinib broadly inhibits HIV-1 reactivation in vitro and ex vivo.
Fig. 3: Ripretinib does not cause apparent cytotoxicity, cell activation, or cell dysfunction.
Fig. 4: Multiple drugs targeting C-kit or PDGFRα inhibit the reactivation of HIV-1 provirus.
Fig. 5: Ripretinib inhibits HIV-1 provirus activation by inhibiting the PI3K-AKT and MAPK signaling pathways.
Fig. 6: Ripretinib inhibits HIV-1 proviral reactivation by suppressing cellular chromatin opening.

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Acknowledgements

We thank all the participants who donated blood samples for this study. This work was supported by National Key R&D Program of China (2021YFC2301903), National Natural Science Foundation of China (32070159, 82302514 to JFC), Science and Technology Projects of Guangdong Province of China (2021B1212030012), the Advanced Medical Technology Center Program of The First Affiliated Hospital of Sun Yat-sen University to KD, and the Nurturing Program of Key Laboratory of Tropical Disease Control of Ministry of Education (SYSU) to JJC.

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  1. These authors contributed equally: Jin-feng Cai, Jia-sheng Zhou, Zhuo-yue Meng

Authors and Affiliations

  1. Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Jin-feng Cai, Jia-sheng Zhou, Zhuo-yue Meng, Zi-qi Wu, Jia-cong Zhao, Hai-xiang Peng, Xin-yu Liang, Jun-jian Chen & Kai Deng

  2. Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Jin-feng Cai, Jia-sheng Zhou, Zhuo-yue Meng, Zi-qi Wu, Jia-cong Zhao, Hai-xiang Peng, Xin-yu Liang, Jun-jian Chen & Kai Deng

  3. Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Pei-pei Wang

  4. Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Kai Deng

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Contributions

KD, JSZ, JFC, and JJC conceived and supervised the project. PPW provided the clinical samples. JSZ, PPW, JFC and ZYM performed the experiments. JFC, ZQW and JCZ analyzed the data. JFC, HXP and XYL edited figures and tables. JSZ, PPW and JFC wrote the manuscript. KD revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Jun-jian Chen, Pei-pei Wang or Kai Deng.

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Cai, Jf., Zhou, Js., Meng, Zy. et al. Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01282-z

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