title: Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition.
abstract: The persistence of HIV in resting memory CD4+T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Xiao-Yan
authors: XY
authors: Pan
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Wei
authors: W
authors: Zhao
authors: the Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China.
authors: Chun-Yan
authors: CY
authors: Wang
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Jian
authors: J
authors: Lin
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Xiao-Yun
authors: XY
authors: Zeng
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Ru-Xia
authors: RX
authors: Ren
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Keng
authors: K
authors: Wang
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
authors: Tian-Rong
authors: TR
authors: Xun
authors: the Department of Biochemistry, Weizmann Science Institute, Rehovot 76100, Israel, and Yechiel.Shai@weizmann.ac.il.
authors: Yechiel
authors: Y
authors: Shai
authors: From the Guangdong Provincial Key Laboratory of Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China, liusw@smu.edu.cn.|the State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, 510515 Guangzhou, China.
authors: Shu-Wen
authors: SW
authors: Liu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D061805:Transcription Elongation, Genetic / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects* / Q000502:physiology; D017735:Virus Latency / Q000187:drug effects* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D061988:Proteasome Inhibitors; D014157:Transcription Factors; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D046988:Proteasome Endopeptidase Complex
keywords: Heat shock factor protein 1 (HSF1); cyclin-dependent kinase (CDK); heat shock protein 90 (Hsp90); human immunodeficiency virus (HIV); latency reversing agent; p-TEFb; proteasome