气候变化领域集成服务门户(CCPortal): Screening for gene expression fluctuations reveals latency-promoting agents of HIV

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DOI	10.1073/pnas.2012191118
	Screening for gene expression fluctuations reveals latency-promoting agents of HIV
	Lu Y.; Bohn-Wippert K.; Pazerunas P.J.; Moy J.M.; Singh H.; Dar R.D.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Upon treatment removal, spontaneous reactivation of latently infected T cells remains a major barrier toward curing HIV. Therapies that reactivate and clear the latent reservoir are only partially effective, while latency-promoting agents (LPAs) used to suppress reactivation and stabilize latency are understudied and lack diversity in their mechanisms of action. Here, we identify additional LPAs using a screen for gene-expression fluctuations (or "noise") that drive cell-fate specification and control HIV reactivation from latency. Single-cell protein dynamics of a minimal HIV gene circuit were monitored with time-lapse fluorescence microscopy. We screened 1,806 drugs, out of which 279 modulate noise magnitude or half autocorrelation time. Next, we tested the strongest noise modulators in a Jurkat T cell latency model and discovered three LPAs that would be overlooked by quantifying their mean expression levels alone. The LPAs reduced reactivation of latency in both Jurkat and primary cell models when challenged by synergistic and potent combinations of HIV activators. The two strongest LPAs, NSC 401005 and NSC 400938, are structurally and functionally related to inhibitors of thioredoxin reductase, a protein involved in maintaining redox balance in host cells. Experiments with multiple functional analogs revealed two additional LPAs, PX12 and tiopronin, and suggest a potential LPA family, within which some are commercially available and Food and Drug Administration-approved. The LPAs presented here may provide new strategies to complement antiretroviral treatments. Screening for gene expression noise holds the potential for drug discovery in other diseases. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Biological noise; Drug screen; HIV latency; Latency-promoting agents; Microscopy
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180273
作者单位	Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Chemical Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
推荐引用方式 GB/T 7714	Lu Y.,Bohn-Wippert K.,Pazerunas P.J.,et al. Screening for gene expression fluctuations reveals latency-promoting agents of HIV[J],2021,118(11).
APA	Lu Y.,Bohn-Wippert K.,Pazerunas P.J.,Moy J.M.,Singh H.,&Dar R.D..(2021).Screening for gene expression fluctuations reveals latency-promoting agents of HIV.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Lu Y.,et al."Screening for gene expression fluctuations reveals latency-promoting agents of HIV".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).