2. Academic Validation
  3. PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1

PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1

  • Biochem Pharmacol. 2018 Oct;156:511-523. doi: 10.1016/j.bcp.2018.08.042.
Jian Lin 1,  Xuanxuan Zhang 1,  Wanzhen Lu 1,  Xinfeng Xu 1,  Xiaoyan Pan 2,  Taizhen Liang 1,  Siqin Duan 1,  Yi Chen 1,  Lin Li 1,  Shuwen Liu 3
Affiliations

Affiliations

  • 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, 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, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China.
  • 3 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, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.
PMID: 30170098 DOI: 10.1016/j.bcp.2018.08.042
Abstract

The existence of latent reservoirs of Human Immunodeficiency Virus type-1 (HIV-1) is a major obstacle in eliminating the virus. Thus, an urgent need exists for effective latency reversing agents (LRAs) based on the "shock and kill" strategy. Proteasome inhibitors were recently studied as LRAs, but were considered too toxic for clinical use. Here, we demonstrated that PR-957, a selective immunoproteasome inhibitor, effectively reactivated latent HIV-1 provirus in vitro and ex vivo. Our data also suggests that PR-957 has relatively low cytotoxicity. Furthermore, it does not influence global T cell activation and decreases the expression levels of HIV-1 receptors/co-receptors. We demonstrated synergistic activation of latent HIV-1 with PR-957 and Prostratin (a protein kinase C activator) that alleviated the extent of T cell activation induced by Prostratin. In addition, PR-957 exhibited latency reversing efficacy through activating p-TEFb mediated by HSF-1 pathway. Moreover, PR-957 did not affect the activity of combination antiretroviral therapy (cART) drugs and the PR-957-reactivated virus was effectively inhibited with cART drugs. In conclusion, the immunoproteasome inhibitor PR-957 is a promising candidate LRA for future HIV-1 eradication strategies.

Keywords

HIV-1 latency; Heat shock factor 1; LRAs; PR-957; p-TEFb.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z