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Biochem Pharmacol. 2019 Jun;164:237-251. doi: 10.1016/j.bcp.2019.04.005. Epub 2019 Apr 13.

A novel bromodomain inhibitor, CPI-203, serves as an HIV-1 latency-reversing agent by activating positive transcription elongation factor b.

Author information

1
Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
2
Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China; The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 518107, PR China.
3
Department of Infectious Disease, Guangzhou No. 8 People's Hospital, Guangzhou 510060, PR China.
4
Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: liusw@smu.edu.cn.
5
Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: li75lin@smu.edu.cn.

Abstract

The persistence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs remains a major hurdle for HIV-1 eradication. The "shock and kill" strategy relies on the drug-mediated reversion of HIV-1 latency and the subsequent death of HIV-producing cells. Unfortunately, none of the agents currently in use possess a sufficient potency to reactivate latent virus or eliminate the latent HIV-1 reservoir in vivo. Here, we demonstrated that a promising specific bromodomain and extraterminal domain inhibitor, CPI-203, could potently reactivate latent HIV-1 in different latently infected cell lines with minimal cytotoxicity by activating the positive transcription elongation factor b signaling pathway. Notably, CPI-203 exhibited synergism in latent HIV-1 reactivation and alleviated the HIV-1-induced "cytokine storm" when used in combination with the protein kinase C (PKC) agonist prostratin. These findings highlight that CPI-203 shows promise as a novel, safe candidate for the design of targeted strategies to "shock and kill" HIV-1 and thus represents a potential functional cure.

KEYWORDS:

CPI-203; Latency-reversing agent; Latent HIV-1; Shock and kill; p-TEFb

PMID:
30991051
DOI:
10.1016/j.bcp.2019.04.005

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