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

Mudit Tyagi1, Sergey Iordanskiy2, Tatyana Ammosova3,4,5

  • 1Department of Medicine, The George Washington University, Washington, DC, 2003, USA. tmudit@email.gwu.edu.

Retrovirology
|July 17, 2015
PubMed
Abstract

Insights

Researchers developed novel small molecules that reactivate latent HIV-1 by targeting protein phosphatase-1 (PP1), enhancing viral transcription and offering a potential cure for HIV.

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • Human immunodeficiency virus type 1 (HIV-1) establishes latent reservoirs by integrating into host DNA, hindering eradication efforts.
  • Reactivation of latent HIV-1 requires transcriptional activation, often impaired in infected cells due to low levels of transcription factors like P-TEFb (CDK9/cyclin T1).
  • Protein phosphatase-1 (PP1) has been shown to regulate HIV-1 transcription by modulating CDK9 phosphorylation, and novel compounds targeting PP1 have been developed.

Purpose of the Study:

  • To develop and evaluate a new class of small molecular compounds targeting a non-catalytic site of PP1 for HIV-1 reactivation.
  • To investigate the mechanism by which these compounds reactivate latent HIV-1, focusing on PP1 activity and CDK9 phosphorylation.

Main Methods:

  • Synthesis and testing of novel sulfonamide-containing compounds, including a specific small molecule activator of PP1 (SMAPP1).
  • Assessing HIV-1 replication and latent reservoir reactivation in acutely and chronically infected cells (cultured and primary).
  • In vitro assays to confirm SMAPP1 interaction with PP1 and its effect on PP1 activity, CDK9 phosphorylation, and protein expression via proteomic analysis. Docking analysis was used to identify the binding site.

Main Results:

  • A novel class of sulfonamide compounds, including SMAPP1, demonstrated activation of HIV-1 in both acute and latent infections.
  • SMAPP1 effectively reactivated latent HIV-1 in chronically infected cells and increased HIV-1 replication.
  • SMAPP1 enhanced PP1 activity, increased phosphorylation of CDK9 at specific residues (Ser90 and Thr186), and led to the upregulation of PP1 and P-TEFb related proteins.

Conclusions:

  • A novel class of PP1-targeting compounds, exemplified by SMAPP1, can reactivate latent HIV-1 provirus.
  • These compounds work by enhancing PP1 activity, increasing CDK9 phosphorylation, and boosting HIV transcription.
  • This discovery presents a promising new therapeutic strategy for eradicating latent HIV-1 reservoirs.

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