1. Academic Validation
  2. A novel selective histone deacetylase I inhibitor CC-4a activates latent HIV-1 through NF-κB pathway

A novel selective histone deacetylase I inhibitor CC-4a activates latent HIV-1 through NF-κB pathway

  • Life Sci. 2021 Feb 15;267:118427. doi: 10.1016/j.lfs.2020.118427.
Wanzhen Lu 1 Chan Yang 1 Xinfeng Xu 1 Chen Chen 2 Xuben Hou 3 Hao Fang 4 Shuwen Liu 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China; Department of Chemistry, New York University, New York, NY 10003, United States.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China. Electronic address: haofangcn@sdu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.
Abstract

Aims: The fact that HIV-1 inside human bodies can perform reverse transcription and integrate resultant DNA into host chromosome remains a challenge in AIDS treatment. "Shock and kill" strategy was proposed to achieve the functional cure, which requested latency reactivating agents (LRAs) to reactivate latent HIV-1 and then extirpate viruses and infected cells with Antiviral agents and the immune system. However, there are no feasible LRAs clinically applied. Herein, we examined a synthesized HDAC I inhibitor, CC-4a, in reactivating latent HIV-1 and investigated its mechanisms.

Materials and methods: Two HIV-1 infected cell models and human PBMCs were used in this study. Flow cytometry, ELISA, luciferase, and RT-PCR assay were used to analyze the expression of viral protein and mRNA. The mechanisms were explored by using cytoplasmic nuclear protein isolation and western blotting assays.

Key findings: CC-4a could successfully reactivate latent HIV-1 at the protein and gene levels with low cytotoxicity. Intriguingly, CC-4a showed the ability to induce Apoptosis in HIV-1 infected cell models. CC-4a exerted a synergistic activation effect with prostratin without triggering global T cell activation and inflammatory factor storm. It was further found that CC-4a down-regulated the expressions of CCR5 and CD4. Moreover, CC-4a together with Antiviral drugs was proved to antagonize HIV-1 without mutual interference. Finally, the enhanced histone acetylation and activated NF-κB pathway were detected in CC-4a mechanisms.

Significance: The results suggested that CC-4a activated latent HIV-1 and showed promising clinical applications, demonstrating that CC-4a played a role in HIV-1 eradication in "shock and kill" strategy.

Keywords

CC-4a; HIV-1 latency; LRAs; NF-κB pathway; Selective HDAC I inhibitor; “shock and kill” strategy.

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