Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1
| Autor: | Namita Kumari, Yasemin Saygideger Kont, Kahli A. Smith, Aykut Üren, Sergei Nekhai, Andrey V. Ilatovskiy, Michael Petukhov, Mudit Tyagi, Sergey Iordanskiy, Tatyana Ammosova, Dmytro Kovalskyy, Andrey Ivanov, Denitra Breuer, Fatah Kashanchi |
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| Rok vydání: | 2015 |
| Předmět: |
Proteomics
Cyclin T1 HL-60 Cells macromolecular substances Biology Antiviral Agents Models Biological environment and public health 03 medical and health sciences Proviruses Transcription (biology) Protein Phosphatase 1 Virology Virus latency medicine Humans Positive Transcriptional Elongation Factor B Phosphorylation Binding site Transcription factor Cells Cultured 030304 developmental biology Sulfonamides 0303 health sciences Research 030302 biochemistry & molecular biology NF-kappa B Virus Activation Provirus Isoquinolines medicine.disease Cyclin-Dependent Kinase 9 Virus Latency 3. Good health Molecular Docking Simulation enzymes and coenzymes (carbohydrates) Infectious Diseases HIV-1 Protein Binding |
| Zdroj: | Retrovirology |
| ISSN: | 1742-4690 |
| DOI: | 10.1186/s12977-015-0190-4 |
| Popis: | Background 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 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. Results 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. Conclusion 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. |
| Databáze: | OpenAIRE |
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