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Retrovirology. 2015 Jul 16;12:63. doi: 10.1186/s12977-015-0190-4.

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

Author information

1
Department of Medicine, The George Washington University, Washington, DC, 2003, USA. tmudit@email.gwu.edu.
2
National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, 20110, USA. siordans@gmu.edu.
3
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. tatiana.ammosova@howard.edu.
4
Department of Medicine, Howard University, Washington, DC, 20059, USA. tatiana.ammosova@howard.edu.
5
Yakut Science Center for Complex Medical Problems, Yakutsk, 677019, Russia. tatiana.ammosova@howard.edu.
6
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. namita.kumari@howard.edu.
7
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. KASmith8403@aol.com.
8
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. denitra.breuer@gmail.com.
9
Division of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute, Gatchina, Russia. andreyi@omrb.pnpi.spb.ru.
10
Instiute of Nanobiotechnologies, St. Petersburg State Polytechnical University, St. Petersburg, Russia. andreyi@omrb.pnpi.spb.ru.
11
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA. ys452@georgetown.edu.
12
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. Andrei.ivanov@howard.edu.
13
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA. au26@georgetown.edu.
14
Department of Biochemistry and Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA. d.kovalskyy@gmail.com.
15
Division of Molecular and Radiation Biophysics, Petersburg Nuclear Physics Institute, Gatchina, Russia. michael.petukhov@yandex.ru.
16
Instiute of Nanobiotechnologies, St. Petersburg State Polytechnical University, St. Petersburg, Russia. michael.petukhov@yandex.ru.
17
National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, 20110, USA. fkashanc@gmu.edu.
18
Center for Sickle Cell Disease, Howard University, 1840 7th Street, N.W. HURB1, Suite 202, Washington, DC, 20059, USA. snekhai@howard.edu.
19
Department of Medicine, Howard University, Washington, DC, 20059, USA. snekhai@howard.edu.

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.

PMID:
26178009
PMCID:
PMC4504130
DOI:
10.1186/s12977-015-0190-4
[Indexed for MEDLINE]
Free PMC Article

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