title: Kinase control prevents HIV-1 reactivation in spite of high levels of induced NF-κB activity.
abstract: Despite its clinical importance, the molecular biology of HIV-1 latency control is at best partially understood, and the literature remains conflicting. The most recent description that latent HIV-1 is integrated into actively expressed host genes has further confounded the situation. This lack of molecular understanding complicates our efforts to identify therapeutic compounds or strategies that could reactivate latent HIV-1 infection in patients, a prerequisite for the eradication of HIV-1 infection. Currently, many therapeutic development efforts operate under the assumption that a restrictive histone code could govern latent infection and that either dissipation of the histone-based restrictions or NF-κB activation could be sufficient to trigger HIV-1 reactivation. We here present data that suggest an additional, higher level of molecular control. During a high-content drug screening effort, we identified AS601245 as a potent inhibitor of HIV-1 reactivation in latently infected primary T cells and T cell lines. In either system, AS601245 inhibited HIV-1 reactivation despite high levels of induced NF-κB activation. This finding suggests the presence of a gatekeeper kinase activity that controls latent HIV-1 infection even in the presence of high levels of NF-κB activity. Potential therapeutic stimuli that do not target this gatekeeper kinase will likely fail to trigger efficient system-wide HIV-1 reactivation.
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Takao
authors.initials: T
authors.lastname: Shishido
authors.forename: Alexandra
authors.initials: A
authors.lastname: Duverger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jones
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014157:Transcription Factors; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects
chemical_list: C489138:1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile; D000097:Acetonitriles; D052160:Benzothiazoles; C476123:HEXIM1 protein, human; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D010770:Phosphotransferases; D042925:Positive Transcriptional Elongation Factor B; D048031:JNK Mitogen-Activated Protein Kinases