Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1. Tyagi, M., Iordanskiy, S., Ammosova, T., Kumari, N., Smith, K., Breuer, D., Ilatovskiy, A., Kont, Y., Ivanov, A., Üren, A., Kovalskyy, D., Petukhov, M., Kashanchi, F., & Nekhai, S. Retrovirology, 12(1):1-17, BioMed Central Ltd., 2015. cited By 13![Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1 [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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. © 2015 Tyagi et al.
@ARTICLE{Tyagi20151,
author={Tyagi, M. and Iordanskiy, S. and Ammosova, T. and Kumari, N. and Smith, K. and Breuer, D. and Ilatovskiy, A.V. and Kont, Y.S. and Ivanov, A. and Üren, A. and Kovalskyy, D. and Petukhov, M. and Kashanchi, F. and Nekhai, S.},
title={Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1},
journal={Retrovirology},
year={2015},
volume={12},
number={1},
pages={1-17},
doi={10.1186/s12977-015-0190-4},
note={cited By 13},
url={https://www.scopus.com/inward/record.uri?eid=2-s2.0-84942468554&doi=10.1186%2fs12977-015-0190-4&partnerID=40&md5=8ee259f33c5246c123a47a2b5d90e288},
affiliation={Department of Medicine, The George Washington University, Washington, DC 2003, United States; National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States; Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC 20059, United States; Department of Medicine, Howard University, Washington, DC 20059, United States; Yakut Science Center for Complex Medical Problems, Yakutsk, 677019, Russian Federation; Division of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute, Gatchina, Russian Federation; Instiute of Nanobiotechnologies, St. Petersburg State Polytechnical University, St. Petersburg, Russian Federation; Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States; Department of Biochemistry, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States},
abstract={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. © 2015 Tyagi et al.},
funding_details={Russian Science Foundation14-34-00023},
funding_details={National Institutes of Health1P50HL118006},
funding_details={National Institutes of Health1R01HL125005},
funding_details={National Institutes of Health5G12MD007597},
funding_details={National Institutes of Health5R03DA033900-02},
funding_details={National Institute on Drug Abuse5R21DA033924-02},
funding_details={National Institutes of HealthF31NS086453},
funding_details={National Institutes of HealthR01AI043894},
funding_details={National Institutes of HealthR21 AI114490},
funding_details={National Institutes of HealthR21AI13140},
funding_details={National Institutes of HealthU19AI109664},
correspondence_address1={Nekhai, S.; Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, United States; email: snekhai@howard.edu},
publisher={BioMed Central Ltd.},
issn={17424690},
pubmed_id={26178009},
language={English},
abbrev_source_title={Retrovirology},
document_type={Article},
source={Scopus},
}
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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. © 2015 Tyagi et al.","funding_details":"National Institutes of HealthU19AI109664","correspondence_address1":"Nekhai, S.; Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. 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