Article

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

Jin-feng Cai1,2, Jia-sheng Zhou1,2, Zhuo-yue Meng1,2, Zi-qi Wu1,2, Jia-cong Zhao1,2, Hai-xiang Peng1,2, Xin-yu Liang1,2, Jun-jian Chen1,2, Pei-pei Wang3, Kai Deng1,2,4
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
2 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
3 Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
4 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Correspondence to: Jun-jian Chen: chenjj366@mail.sysu.edu.cn, Pei-pei Wang: wangpp3@mail.sysu.edu.cn, Kai Deng: dengkai6@mail.sysu.edu.cn,
DOI: 10.1038/s41401-024-01282-z
Received: 26 October 2023
Accepted: 29 March 2024
Advance online: 16 April 2024

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.

Keywords: HIV-1; block and lock; latency-promoting agents; ripretinib; PI3K-AKT-mTOR

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