维甲酸 B 可通过核因子-κB（NF-κB）途径重新激活潜伏的人类免疫缺陷病毒（HIV-1）。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-19 DOI:10.1016/j.phymed.2025.156667

Ziyao Wu , Kang Ding , Wenli Liu , Hong He , Meiyun Chen , Mingxin Chen , Liwen Zhang , Chunyan Wang , Weiku Zhang , Lin Li

{"title":"维甲酸 B 可通过核因子-κB（NF-κB）途径重新激活潜伏的人类免疫缺陷病毒（HIV-1）。","authors":"Ziyao Wu , Kang Ding , Wenli Liu , Hong He , Meiyun Chen , Mingxin Chen , Liwen Zhang , Chunyan Wang , Weiku Zhang , Lin Li","doi":"10.1016/j.phymed.2025.156667","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Combination antiretroviral therapy (cART) and latency-reversing agents (LRAs) have not achieved a successful cure of HIV infection, due to latent HIV reservoir for the former, and insufficient efficacy and adverse side effects for the latter. Therefore, candidate LRAs with high antiviral efficacy and low cytotoxicity are critical for achieving a functional cure of HIV-1 infection.</div></div><div><h3>Purpose</h3><div>To identify promising flavonoids with dual functions in reactivating latent HIV-1 and inhibiting viral infection, and to explore the mechanisms involved therein.</div></div><div><h3>Methods</h3><div>We screened 21 flavonoids from <em>Stellera chamaejasme</em> and selected wikstrol B as a promising LRA candidate. The effects of the candidate on latent HIV-1 reactivation were assessed using enzyme-linked immunosorbent assay (ELISA), reverse-transcription quantitative PCR (RT-qPCR), and flow cytometry. Its cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, western blot (WB) analysis, confocal microscopy and chromatin immunoprecipitation (ChIP) assay were applied for mechanism exploration. Anti-HIV-1 activity was assessed with ELISA, and the effect of wikstrol B on the Vif/hA3G complex was evaluated by co-immunoprecipitation (Co-IP) assay. Additionally, synergy of wikstrol B with cART drugs or other LRAs were also tested.</div></div><div><h3>Results</h3><div>Wikstrol B effectively reversed HIV-1 latency in both latently infected cell lines and primary CD4<sup>+</sup> T cells at low micromolar concentrations with minimal cytotoxicity. As for mechanisms, wikstrol B specifically induced HIV-1 long terminal repeat (LTR) transactivation and reactivated latent HIV-1 transcription by modulating the NF-κB signaling pathway. Additionally, wikstrol B demonstrated potent inhibitory activity against the laboratory-adapted HIV-1<sub>IIIB</sub> strain by blocking Vif-mediated degradation.</div></div><div><h3>Conclusion</h3><div>Wikstrol B is capable of both reactivating latent HIV-1 and inhibiting HIV-1 infection with few adverse effects, and may be applied, preferably in synergistic combination with cART drugs and other LRAs, in the “shock and kill” strategy for treating Acquired Immune Deficiency Syndrome (AIDS).</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156667"},"PeriodicalIF":6.7000,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Wikstrol B reactivates latent human immunodeficiency virus (HIV-1) via the nuclear factor-κB (NF-κB) pathway\",\"authors\":\"Ziyao Wu , Kang Ding , Wenli Liu , Hong He , Meiyun Chen , Mingxin Chen , Liwen Zhang , Chunyan Wang , Weiku Zhang , Lin Li\",\"doi\":\"10.1016/j.phymed.2025.156667\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Combination antiretroviral therapy (cART) and latency-reversing agents (LRAs) have not achieved a successful cure of HIV infection, due to latent HIV reservoir for the former, and insufficient efficacy and adverse side effects for the latter. Therefore, candidate LRAs with high antiviral efficacy and low cytotoxicity are critical for achieving a functional cure of HIV-1 infection.</div></div><div><h3>Purpose</h3><div>To identify promising flavonoids with dual functions in reactivating latent HIV-1 and inhibiting viral infection, and to explore the mechanisms involved therein.</div></div><div><h3>Methods</h3><div>We screened 21 flavonoids from <em>Stellera chamaejasme</em> and selected wikstrol B as a promising LRA candidate. The effects of the candidate on latent HIV-1 reactivation were assessed using enzyme-linked immunosorbent assay (ELISA), reverse-transcription quantitative PCR (RT-qPCR), and flow cytometry. Its cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, western blot (WB) analysis, confocal microscopy and chromatin immunoprecipitation (ChIP) assay were applied for mechanism exploration. Anti-HIV-1 activity was assessed with ELISA, and the effect of wikstrol B on the Vif/hA3G complex was evaluated by co-immunoprecipitation (Co-IP) assay. Additionally, synergy of wikstrol B with cART drugs or other LRAs were also tested.</div></div><div><h3>Results</h3><div>Wikstrol B effectively reversed HIV-1 latency in both latently infected cell lines and primary CD4<sup>+</sup> T cells at low micromolar concentrations with minimal cytotoxicity. As for mechanisms, wikstrol B specifically induced HIV-1 long terminal repeat (LTR) transactivation and reactivated latent HIV-1 transcription by modulating the NF-κB signaling pathway. Additionally, wikstrol B demonstrated potent inhibitory activity against the laboratory-adapted HIV-1<sub>IIIB</sub> strain by blocking Vif-mediated degradation.</div></div><div><h3>Conclusion</h3><div>Wikstrol B is capable of both reactivating latent HIV-1 and inhibiting HIV-1 infection with few adverse effects, and may be applied, preferably in synergistic combination with cART drugs and other LRAs, in the “shock and kill” strategy for treating Acquired Immune Deficiency Syndrome (AIDS).</div></div>\",\"PeriodicalId\":20212,\"journal\":{\"name\":\"Phytomedicine\",\"volume\":\"141 \",\"pages\":\"Article 156667\"},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2025-03-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Phytomedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0944711325003071\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325003071","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

背景联合抗逆转录病毒疗法（cART）和潜伏期逆转剂（LRAs）未能成功治愈HIV感染，前者的原因是HIV潜伏库，后者的原因是疗效不足和不良副作用。因此，具有高抗病毒疗效和低细胞毒性的候选LRA对于实现HIV-1感染的功能性治愈至关重要。方法我们从Stellera chamaejasme中筛选出21种黄酮类化合物，并选择了wikstrol B作为有希望的候选LRA。我们使用酶联免疫吸附试验（ELISA）、反转录定量 PCR（RT-qPCR）和流式细胞术评估了候选化合物对潜伏 HIV-1 再激活的影响。其细胞毒性通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑（MTT）试验进行评估。流式细胞术、Western 印迹（WB）分析、共聚焦显微镜和染色质免疫沉淀（ChIP）测定被用于机制探索。通过酶联免疫吸附（ELISA）法评估了抗 HIV-1 活性，并通过共沉淀（Co-IP）法评估了威克司醇 B 对 Vif/hA3G 复合物的影响。结果威克司醇 B 在低微摩尔浓度下能有效逆转潜伏感染细胞系和原代 CD4+ T 细胞的 HIV-1 潜伏期，且细胞毒性极低。在作用机制方面，甲地孕酮 B 通过调节 NF-κB 信号通路，特异性地诱导了 HIV-1 长末端重复序列（LTR）的反式激活，并重新激活了潜伏的 HIV-1 转录。此外，Wikstrol B 通过阻断 Vif 介导的降解，对实验室改良的 HIV-1IIIB 株表现出了强大的抑制活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Wikstrol B reactivates latent human immunodeficiency virus (HIV-1) via the nuclear factor-κB (NF-κB) pathway

查看原文本刊更多论文

Wikstrol B reactivates latent human immunodeficiency virus (HIV-1) via the nuclear factor-κB (NF-κB) pathway

Background

Combination antiretroviral therapy (cART) and latency-reversing agents (LRAs) have not achieved a successful cure of HIV infection, due to latent HIV reservoir for the former, and insufficient efficacy and adverse side effects for the latter. Therefore, candidate LRAs with high antiviral efficacy and low cytotoxicity are critical for achieving a functional cure of HIV-1 infection.

Purpose

To identify promising flavonoids with dual functions in reactivating latent HIV-1 and inhibiting viral infection, and to explore the mechanisms involved therein.

Methods

We screened 21 flavonoids from Stellera chamaejasme and selected wikstrol B as a promising LRA candidate. The effects of the candidate on latent HIV-1 reactivation were assessed using enzyme-linked immunosorbent assay (ELISA), reverse-transcription quantitative PCR (RT-qPCR), and flow cytometry. Its cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, western blot (WB) analysis, confocal microscopy and chromatin immunoprecipitation (ChIP) assay were applied for mechanism exploration. Anti-HIV-1 activity was assessed with ELISA, and the effect of wikstrol B on the Vif/hA3G complex was evaluated by co-immunoprecipitation (Co-IP) assay. Additionally, synergy of wikstrol B with cART drugs or other LRAs were also tested.

Results

Wikstrol B effectively reversed HIV-1 latency in both latently infected cell lines and primary CD4⁺ T cells at low micromolar concentrations with minimal cytotoxicity. As for mechanisms, wikstrol B specifically induced HIV-1 long terminal repeat (LTR) transactivation and reactivated latent HIV-1 transcription by modulating the NF-κB signaling pathway. Additionally, wikstrol B demonstrated potent inhibitory activity against the laboratory-adapted HIV-1_IIIB strain by blocking Vif-mediated degradation.

Conclusion

Wikstrol B is capable of both reactivating latent HIV-1 and inhibiting HIV-1 infection with few adverse effects, and may be applied, preferably in synergistic combination with cART drugs and other LRAs, in the “shock and kill” strategy for treating Acquired Immune Deficiency Syndrome (AIDS).

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.