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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.

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    • Authors

    Wolschendorf F, Bosque A, Shishido T, Duverger A, Jones J, Planelles V, Kutsch O

    Institution

    Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

    Source

    Journal of virology 86:8 2012 Apr pg 4548-58

    MeSH

    Acetonitriles
    Benzothiazoles
    Cell Line
    Gene Expression Regulation
    HIV-1
    Humans
    JNK Mitogen-Activated Protein Kinases
    NF-kappa B
    Phosphotransferases
    Positive Transcriptional Elongation Factor B
    Protein Binding
    Protein Kinase Inhibitors
    RNA-Binding Proteins
    Signal Transduction
    T-Lymphocytes
    Virus Activation
    Virus Latency

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22345467