A Natural Product from Polygonum cuspidatum Sieb. Et Zucc. Promotes Tat-Dependent HIV Latency Reversal through Triggering P-TEFb's Release from 7SK snRNP

• Published in: PloS one 2015-11, Vol.10 (11), p.e0142739
• Main Authors: Wang, Cong, Yang, Shuiyuan, Lu, Huasong, You, Hongchao, Ni, Man, Shan, Wenjun, Lin, Ting, Gao, Xiang, Chen, Haifeng, Zhou, Qiang, Xue, Yuhua
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antiretroviral agents; Antiretroviral drugs; Azepines - pharmacology; Biological Products - pharmacology; Biology; Cell Survival - drug effects; Chemical compounds; Coding; Drug Synergism; Fallopia japonica - chemistry; Gene expression; Green Fluorescent Proteins - metabolism; Herbal medicine; Herbs; Highly active antiretroviral therapy; HIV; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Human populations; Humans; Jurkat Cells; Latency; Latent infection; Lymphocytes; Lymphocytes T; Medicinal herbs; Medicinal plants; Natural products; NF-κB protein; Pharmaceutical sciences; Phorbol Esters - pharmacology; Polygonum cuspidatum; Positive Transcriptional Elongation Factor B - metabolism; Proanthocyanidins - pharmacology; Proteins; Proviruses; Reservoirs; Ribonucleoproteins (small nuclear); Ribonucleoproteins, Small Nuclear - metabolism; RNA polymerase; tat Gene Products, Human Immunodeficiency Virus - metabolism; Tat protein; Terminal Repeat Sequences - genetics; Time Factors; Toxicity; Transcription activation; Transcription, Genetic - drug effects; Triazoles - pharmacology; Virus Latency - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142739

The latent reservoirs of HIV represent a major impediment to eradication of HIV/AIDS. To overcome this problem, agents that can activate latent HIV proviruses have been actively sought after, as they can potentially be used in combination with the highly active antiretroviral therapy (HAART) to eliminate the latent reservoirs. Although several chemical compounds have been shown to activate latency, they are of limited use due to high toxicity and poor clinical outcomes. In an attempt to identify natural products as effective latency activators from traditional Chinese medicinal herbs that have long been widely used in human population, we have isolated procyanidin C-13,3',3"-tri-O-gallate (named as REJ-C1G3) from Polygonum cuspidatum Sieb. et Zucc., that can activate HIV in latently infected Jurkat T cells. REJ-C1G3 preferentially stimulates HIV transcription in a process that depends on the viral encoded Tat protein and acts synergistically with prostratin (an activator of the NF-κB pathway) or JQ1 (an inhibitor of Brd4) to activate HIV latency. Our mechanistic analyses further show that REJ-C1G3 accomplishes these tasks by inducing the release of P-TEFb, a host cofactor essential for Tat-activation of HIV transcription, from the cellular P-TEFb reservoir 7SK snRNP.