BI-2536 and BI-6727, dual Polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV-1

Jin Gohda,Xialin Xie,Takaomi Ishida,Jun-Ichiro Inoue,Yasushi Kawaguchi,Hiroaki Takeuchi,Kai Liu,Kazuo Suzuki

doi:10.1038/s41598-018-21942-5

Jin Gohda, Xialin Xie + Show 6 more

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https://doi.org/10.1038/s41598-018-21942-5

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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.

Highlights

The use of highly active antiretroviral therapy (HAART) has contributed considerably to extending the life span of patients infected with human immunodeficiency virus type 1 (HIV-1) by preventing acquired immunodeficiency syndrome (AIDS) from developing
Jurkat T cell lines have been widely used as HIV-1 latent T cell models, contributing to clarifying the mechanisms of viral latency and screening of LRAs28
To examine whether bromodomain inhibition by BI-2536 and BI-6727 is involved in the HIV-1 long terminal repeat (LTR) activation, we investigated the effect of combination treatment with BI inhibitors and JQ1 or an Histone deacetylase (HDAC) inhibitor, SAHA

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The use of highly active antiretroviral therapy (HAART) has contributed considerably to extending the life span of patients infected with human immunodeficiency virus type 1 (HIV-1) by preventing acquired immunodeficiency syndrome (AIDS) from developing. A major barrier to viral eradication is the persistence of latently infected reservoirs that can evade both the host antiviral response and HAART1. Latent HIV-1 is “shocked”; in other words, silent proviruses in the latent reservoirs are forcibly reactivated by treatment with latency reversing agents (LRAs) during HAART to prevent susceptible cells from becoming infected with the newly produced viruses. Many small molecules and agents have been suggested as potential LRAs for the “shock and kill” strategy[6,7]. Based on their functional mechanisms, these agents can be broadly categorized as follows: (i) epigenetic modifiers of the HIV-1 LTR promoter region; (ii) activators of transcriptional factors, such as nuclear factor ims.u-tokyo.ac.jp) www.nature.com/scientificreports/. PKC agonists activate transcriptional factors, such as NF-κB and AP-1, which bind to their recognition sites within the LTR and activate viral mRNA transcription[12]

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