Abstract |
HIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The " shock and kill" strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 ( volasertib), which are currently undergoing clinical trials against various cancers. BI-2536 and BI-6727 significantly reactivated silenced HIV-1 provirus at both the mRNA and protein level in two latently infected model cell lines (ACH2 and U1). BI-2536 dramatically reactivated transcription of latent HIV-1 provirus in peripheral blood mononuclear cells derived from infected patients. Long terminal repeat activation by the inhibitors was associated with bromodomain rather than PLK inhibition. We also found that BI-2536 synergistically activates the latent provirus in combination with SAHA, a histone deacetylase inhibitor, or the non-tumour-promoting phorbol ester prostratin. Our findings strongly suggest that BI-2536 and BI-6727 are potent LRAs for the " shock and kill" HIV-1 eradication strategy.
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Authors | Jin Gohda, Kazuo Suzuki, Kai Liu, Xialin Xie, Hiroaki Takeuchi, Jun-Ichiro Inoue, Yasushi Kawaguchi, Takaomi Ishida |
Journal | Scientific reports
(Sci Rep)
Vol. 8
Issue 1
Pg. 3521
(02 23 2018)
ISSN: 2045-2322 [Electronic] England |
PMID | 29476067
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- BI 2536
- BI 6727
- Drug Combinations
- Histone Deacetylase Inhibitors
- Phorbol Esters
- Protein Kinase Inhibitors
- Pteridines
- RNA, Messenger
- RNA, Viral
- Vorinostat
- prostratin
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Topics |
- Cell Line, Tumor
- Drug Combinations
- Gene Expression Regulation, Viral
(drug effects)
- HIV-1
(drug effects, genetics, growth & development)
- Histone Deacetylase Inhibitors
(pharmacology)
- Host-Pathogen Interactions
(drug effects, genetics)
- Humans
- Inhibitory Concentration 50
- Leukocytes, Mononuclear
(drug effects, metabolism, virology)
- Lymphocytes
(drug effects, metabolism, virology)
- Monocytes
(drug effects, metabolism, virology)
- Phorbol Esters
(pharmacology)
- Primary Cell Culture
- Protein Domains
- Protein Kinase Inhibitors
(pharmacology)
- Pteridines
(pharmacology)
- RNA, Messenger
(agonists, genetics, metabolism)
- RNA, Viral
(agonists, genetics, metabolism)
- THP-1 Cells
- Transcription, Genetic
(drug effects)
- Virus Activation
(drug effects, genetics)
- Virus Latency
(drug effects, genetics)
- Vorinostat
(pharmacology)
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