Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui

Wang, Pengfei; Lu, Panpan; Qu, Xin; Shen, Yinzhong; Zeng, Hulie; Zhu, Xiaoli; Zhu, Yuqi; Li, Xian; Wu, Hao; Xu, Jianqing; Lu, Hongzhou; Ma, Zhongjun; Zhu, Huanzhang

doi:10.1038/s41598-017-07157-0

Cited by 42 publications

(34 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, kansui exhibits a strong synergy with HDACis or BETis, indicating that kansui can be used in combination with these LRAs to achieve a high level of HIV expression in latently infected cells [ 78 ]. Finally, using natural products such as kansui would greatly reduce the cost of treatment, which would contribute to providing affordable options to the patients in areas where expensive Western medicines cannot be accessible [ 123 ].…”

Section: Development Of Specific Therapymentioning

confidence: 99%

HIV Tat/P-TEFb Interaction: A Potential Target for Novel Anti-HIV Therapies

2018

View full text Add to dashboard Cite

Transcription is a crucial step in the life cycle of the human immunodeficiency virus type 1 (HIV 1) and is primarily involved in the maintenance of viral latency. Both viral and cellular transcription factors, including transcriptional activators, suppressor proteins and epigenetic factors, are involved in HIV transcription from the proviral DNA integrated within the host cell genome. Among them, the virus-encoded transcriptional activator Tat is the master regulator of HIV transcription. Interestingly, unlike other known transcriptional activators, Tat primarily activates transcriptional elongation and initiation by interacting with the cellular positive transcriptional elongation factor b (P-TEFb). In this review, we describe the molecular mechanism underlying how Tat activates viral transcription through interaction with P-TEFb. We propose a novel therapeutic strategy against HIV replication through blocking Tat action.

show abstract

Section: Development Of Specific Therapymentioning

confidence: 99%

HIV Tat/P-TEFb Interaction: A Potential Target for Novel Anti-HIV Therapies

2018

View full text Add to dashboard Cite

show abstract

“…Figure 1A displays the structure of RVX-208 and PFI-1. To determine the effect of RVX-208 and PFI-1 on latent HIV-1 reactivation, we used J-Lat C11 cell line in which transcriptional activation of the latent provirus can be detected in individual cells by flow cytometry, since these cells harbor full-length latent HIV-1 provirus containing GFP gene in place of nef 13 , 24 – 27 . We found that both RVX-208 and PFI-1 robustly increased the level of GFP expression.…”

Section: Resultsmentioning

confidence: 99%

“…These assays were approved by Shanghai Public Health Clinical Center and Shanghai Changhai Hospital. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh whole blood by density gradient centrifugation using Lympholyte®-H Cell Separation Media (Cedarlane Laboratories) as previously described 13 , 27 . CD4+ T cells were isolated from PBMCs by negative selection using CD4+ T cell Isolation Kit (Miltenyi Biotech).…”

Section: Methodsmentioning

confidence: 99%

BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency

Shen

Yang

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro. The two BET inhibitors also reactivated HIV-1 transcription in cART treated patient-derived resting CD4+ T cells ex vivo, without influence on global immune cell activation. Our findings, in combination with previous reports, further confirm that BET inhibitors are a group of leading compounds for combating HIV-1 latency for viral eradication.

show abstract

“…C11 cells are a type of HIV-1 latently infected cells constructed by our lab. 8 , 27 , 28 , 29 , 30 , 31 , 32 YA were derived from Jurkat T cells infected with HIV-1 pseudovirus carrying the eGFP reporter gene. 8 , 27 Both of them were cultured in RPMI 1640 medium with 10% FBS (Gibco, Grand Island, NY, USA), 100 U/mL penicillin, and 100 μg/mL streptomycin (Invitrogen, Shanghai, China) at 37°C under 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells

Liu

et al. 2018

Molecular Therapy - Nucleic Acids

Self Cite

View full text Add to dashboard Cite

Highly active anti-retroviral therapy (HAART) cannot clear infected cells harboring HIV-1 proviral DNA from HIV-1-infected patients. We previously demonstrated that zinc-finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells by targeting long terminal repeats (LTRs), a novel and alternative antiretroviral strategy for eradicating HIV-1 infection. To prevent unwanted off-target effects from constantly expressed ZFNs, in this study, we engineered the expression of ZFNs under the control of HIV-1 LTR, by which ZFN expression can be activated by the HIV-1 (Trans-Activator of Transcription) Tat protein. Our results show that functional expression of ZFNs induced by Tat excise the integrated proviral DNA of HIV-NL4-3-eGFP in approximately 30% of the population of HIV-1-infected cells. The results from HIV-1-infected human primary T cells and latently infected T cells treated with the inducible ZFNs further validated that proviral DNA can be excised. Taken together, positively regulated expression of ZFNs in the presence of HIV-1 Tat may provide a safer and novel implementation of genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells.

show abstract

Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui

Cited by 42 publications

References 100 publications

HIV Tat/P-TEFb Interaction: A Potential Target for Novel Anti-HIV Therapies

HIV Tat/P-TEFb Interaction: A Potential Target for Novel Anti-HIV Therapies

BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency

Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells

Contact Info

Product

Resources

About