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Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

ABSTRACT: HIV-1 escapes antiretroviral drugs by integrating into the host DNA and forming a latent transcriptionally silent HIV-1 provirus. This provirus presents the major hurdle in HIV-1 eradication and cure. Transcriptional activation, which is prerequisite for reactivation and the eradication of latent proviruses, is impaired in latently infected T cells due to the lack of host transcription factors, primarily NF-?B and P-TEFb (CDK9/cyclin T1). We and others previously showed that protein phosphatase-1 (PP1) regulates HIV-1 transcription by modulating CDK9 phosphorylation. Recently we have developed a panel of small molecular compounds targeting a non-catalytic site of PP1.Here we generated a new class of sulfonamide-containing compounds that activated HIV-1 in acute and latently infected cells. Among the tested molecules, a small molecule activator of PP1 (SMAPP1) induced both HIV-1 replication and reactivation of latent HIV-1 in chronically infected cultured and primary cells. In vitro, SMAPP1 interacted with PP1 and increased PP1 activity toward a recombinant substrate. Treatment with SMAPP1 increased phosphorylation of CDK9's Ser90 and Thr186 residues, but not Ser175. Proteomic analysis showed upregulation of P-TEFb and PP1 related proteins, including PP1 regulatory subunit Sds22 in SMAPP1-treated T cells. Docking analysis identified a PP1 binding site for SMAPP1 located within the C-terminal binding pocket of PP1.We identified a novel class of PP1-targeting compounds that reactivate latent HIV-1 provirus by targeting PP1, increasing CDK9 phosphorylation and enhancing HIV transcription. This compound represents a novel candidate for anti-HIV-1 therapeutics aiming at eradication of latent HIV-1 reservoirs.

SUBMITTER: Tyagi M

PROVIDER: S-EPMC4504130 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

Tyagi Mudit M Iordanskiy Sergey S Ammosova Tatyana T Kumari Namita N Smith Kahli K Breuer Denitra D Ilatovskiy Andrey V AV Kont Yasemin Saygideğer YS Ivanov Andrey A Üren Aykut A Kovalskyy Dmytro D Petukhov Michael M Kashanchi Fatah F Nekhai Sergei S

Retrovirology 20150716

<h4>Background</h4>HIV-1 escapes antiretroviral drugs by integrating into the host DNA and forming a latent transcriptionally silent HIV-1 provirus. This provirus presents the major hurdle in HIV-1 eradication and cure. Transcriptional activation, which is prerequisite for reactivation and the eradication of latent proviruses, is impaired in latently infected T cells due to the lack of host transcription factors, primarily NF-κB and P-TEFb (CDK9/cyclin T1). We and others previously showed that p ...[more]

PMID: 26178009

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Project description:Latent HIV-1 provirus represents the barrier toward a cure for infection and is dependent upon the host RNA Polymerase (Pol) II machinery for reemergence. Here, we find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency-reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to the HIV-1 LTR. Furthermore, HIV-1 expression in response to several latency reversal agents was impaired upon disruption of CDK8 by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Additionally, treatment of CD4+ peripheral blood mononuclear cells isolated from people living with HIV-1 and who are receiving antiretroviral therapy with Senexin A inhibited induction of viral replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases, CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression. IMPORTANCE A cure for HIV-1 infection will require novel therapies that can force elimination of cells that contain copies of the virus genome inserted into the cell chromosome, but which is shut off, or silenced. These are known as latently-infected cells, which represent the main reason why current treatment for HIV/AIDS cannot cure the infection because the virus in these cells is unaffected by current drugs. Our results indicate that chemical inhibitors of Cdk8 also inhibit the expression of latent HIV provirus. Cdk8 is an important enzyme that regulates the expression of genes in response to signals to which cells need to respond and which is produced by a gene that is frequently mutated in cancers. Our observations indicate that Cdk8 inhibitors may be employed in novel therapies to prevent expression from latent provirus, which might eventually enable infected individuals to cease treatment with antiretroviral drugs.

Dataset Information

Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

Publications

Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.

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