title: Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412.
abstract: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis.
  
  
  
  We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells. PKC412 reactivated HIV-1 expression in ACH2 cells in a dose- and time-dependent manner. Our results also suggest that the nuclear factor κB (NF-κB) signaling could be one of cellular pathways activated during PKC412-mediated activation of latent HIV-1 expression. Additionally, combining PKC412 with the HDAC inhibitor vorinostat (VOR) had an additive effect on HIV-1 reactivation in both ACH2 cells and infected resting CD4+ T cells.
  
  
  
  These studies provide evidence that PKC412 is a new compound with the potential for optimization as a latency-reactivator to eradicate HIV-1 infection.
authors: Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.|Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors: Zhujun
authors: Z
authors: Ao
authors: Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors: Rong
authors: R
authors: Zhu
authors: Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
authors: Xiaoli
authors: X
authors: Tan
authors: Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
authors: Lisa
authors: L
authors: Liu
authors: Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
authors: Liyu
authors: L
authors: Chen
authors: Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
authors: Shuiping
authors: S
authors: Liu
authors: Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada. xiao-jian.yao@umanitoba.ca.
authors: XiaoJian
authors: X
authors: Yao
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors; D019311:Staurosporine; C059539:midostaurin
keywords: ACH2 cells; HIV latency; NF-κB signaling; PKC412; Resting CD4+ T cells