Life sciences · 2020
A novel selective histone deacetylase I inhibitor CC-4a activates latent HIV-1 through NF-κB pathway.
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Lu Wanzhen, Yang Chan, Xu Xinfeng, Chen Chen, Hou Xuben, Fang Hao, Liu Shuwen
Аннотация
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.
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.