Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:94104-94116. https://doi.org/10.18632/oncotarget.21585

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Abstract

Hanyu Pan1,*, Panpan Lu1,*, Yinzhong Shen2, Yanan Wang1, Zhengtao Jiang1, Xinyi Yang1, Yangcheng Zhong1, He Yang1, Inam Ulla Khan1, Muya Zhou1, Bokang Li1, Ziyu Zhang1, Jianqing Xu2, Hongzhou Lu2 and Huanzhang Zhu1

1State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China

2Department of Infectious Diseases and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Huanzhang Zhu, email: hzzhu@fudan.edu.cn

Keywords: bromosporine, HIV-1 latency, reactivation, BET inhibitor, CDK9 T-loop

Received: July 12, 2017     Accepted: September 21, 2017     Published: October 06, 2017

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.


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