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: Frank Wolschendorf, Alberto Bosque, Takao Shishido, Alexandra Duverger, Jennifer Jones, Vicente Planelles, Olaf Kutsch
• Journal: Journal of virology (J Virol) Vol. 86 Issue 8 Pg. 4548-58 (Apr 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22345467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile
• Acetonitriles
• Benzothiazoles
• HEXIM1 protein, human
• NF-kappa B
• Protein Kinase Inhibitors
• RNA-Binding Proteins
• Transcription Factors
• Phosphotransferases
• Positive Transcriptional Elongation Factor B
• JNK Mitogen-Activated Protein Kinases

Topics

• Acetonitriles (pharmacology)
• Benzothiazoles (pharmacology)
• Cell Line
• Gene Expression Regulation (drug effects)
• HIV-1 (drug effects, metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Phosphotransferases (antagonists & inhibitors, metabolism)
• Positive Transcriptional Elongation Factor B (metabolism)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• RNA-Binding Proteins (metabolism)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, virology)
• Transcription Factors
• Virus Activation (drug effects)
• Virus Latency (drug effects)