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: Alexandra Duverger, Frank Wolschendorf, Joshua C Anderson, Frederic Wagner, Alberto Bosque, Takao Shishido, Jennifer Jones, Vicente Planelles, Christopher Willey, Randall Q Cron, Olaf Kutsch
• Journal: Journal of virology (J Virol) Vol. 88 Issue 1 Pg. 364-76 (Jan 2014) ISSN: 1098-5514 [Electronic] United States
• PMID: 24155393 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-pim-1

Topics

• Gene Expression Regulation, Viral
• HIV Infections (physiopathology, virology)
• HIV-1 (genetics, physiology)
• Humans
• Jurkat Cells
• Proto-Oncogene Proteins c-pim-1 (genetics, physiology)
• Virus Activation
• Virus Latency