The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells.

Hanyu Pan,Bokang Li,Zhengtao Jiang,Huanzhang Zhu,Yinzhong Shen,Xinyi Yang,Inam Ulla Khan,Panpan Lu,Yanan Wang,Hongzhou Lu,He Yang,Jianqing Xu,Ziyu Zhang,Yangcheng Zhong,Muya Zhou

doi:10.18632/oncotarget.21585

Hanyu Pan, Bokang Li + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.21585

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Abstract

The long-lived latent HIV-1 reservoir is the major barrier for complete cure of Acquired Immune Deficiency Syndrome (AIDS). Here we report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate HIV-1 replication in different latency models alone and more powerful when combined with prostratin or TNF-α. Furthermore, the treatment with bromosporine induced HIV-1 full-length transcripts in resting CD4+ T cells from infected individuals with suppressive antiretroviral therapy (ART) ex vivo, with no obvious cytotoxicity or global activation of T cell. Finally, our data suggest that Tat plays a critical role in the bromosporine-mediated reactivation of latent HIV-1, which involved the increase of CDK9 T-loop phosphorylation. In summary, we found that the BET inhibitor bromosporine, alone or with other activators, might be a candidate for future HIV-1 eradication strategies.

Highlights

Since the recognition of Acquired Immunodeficiency Syndrome (AIDS) in 1981 [1], there is still no winning strategy to completely cure Acquired Immune Deficiency Syndrome (AIDS)
We report that a novel bromodomain and extraterminal domain (BET) inhibitor bromosporine which can broadly target BETs, is able to potently reactivate human immunodeficiency virus (HIV)-1 replication in different latency models alone and more powerful when combined with prostratin or tumor necrosis factor (TNF)-α
The C11 cells were Jurkat cells latently infected with a single provirus integrated into intron of RNA-binding protein with serinerich domain 1 (RNPS1) and encoding the green florescence protein (GFP) under the control of HIV-1 long terminal repeats (LTR) as a marker of HIV-1 expression

Summary

Introduction

Since the recognition of Acquired Immunodeficiency Syndrome (AIDS) in 1981 [1], there is still no winning strategy to completely cure AIDS. According to the report of world health organization (WHO) in 2015, there were approximately 36.7 million people living with HIV-1 (Human Immunodeficiency Virus type 1), the causative agent of the AIDS, except for those who have died of AIDS. Due to the tremendous size of latent reservoirs, which are likely established within days of infection [5], estimated to be 105–106 cells per patient, it will take more than 70 years to eradicate HIV1 if just treated with ART [6, 7]. Elimination of the latent reservoirs of HIV is extremely important to overcome AIDS completely

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