title: Kinase control of latent HIV-1 infection: PIM-1 kinase as a major contributor to HIV-1 reactivation.
abstract: Despite the clinical relevance of latent HIV-1 infection as a block to HIV-1 eradication, the molecular biology of HIV-1 latency remains incompletely understood. We recently demonstrated the presence of a gatekeeper kinase function that controls latent HIV-1 infection. Using kinase array analysis, we here expand on this finding and demonstrate that the kinase activity profile of latently HIV-1-infected T cells is altered relative to that of uninfected T cells. A ranking of altered kinases generated from these kinome profile data predicted PIM-1 kinase as a key switch involved in HIV-1 latency control. Using genetic and pharmacologic perturbation strategies, we demonstrate that PIM-1 activity is indeed required for HIV-1 reactivation in T cell lines and primary CD4 T cells. The presented results thus confirm that kinases are key contributors to HIV-1 latency control. In addition, through mutational studies we link the inhibitory effect of PIM-1 inhibitor IV (PIMi IV) on HIV-1 reactivation to an AP-1 motif in the CD28-responsive element of the HIV-1 long terminal repeat (LTR). The results expand our conceptual understanding of the dynamic interactions of the host cell and the latent HIV-1 integration event and position kinome profiling as a research tool to reveal novel molecular mechanisms that can eventually be targeted to therapeutically trigger HIV-1 reactivation.
authors.affiliation: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Duverger
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Anderson
authors.forename: Frederic
authors.initials: F
authors.lastname: Wagner
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Takao
authors.initials: T
authors.lastname: Shishido
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jones
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.forename: Christopher
authors.initials: C
authors.lastname: Willey
authors.forename: Randall Q
authors.initials: RQ
authors.lastname: Cron
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
mesh_terms: D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000503:physiopathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000502:physiology*; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D051573:Proto-Oncogene Proteins c-pim-1