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Inhibition of human immunodeficiency virus type 1 by niclosamide through mTORC1 inhibition

Nattamon Niyomdecha1,2, Ornpreya Suptawiwat3, Chompunuch Boonarkart1

  • 1Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Heliyon
|June 13, 2020
PubMed

Insights

Niclosamide inhibits HIV-1 replication by disrupting the AMPK-mTORC1 pathway, a mechanism potentially applicable to other viruses. This antiviral action involves downregulating mTORC1 signaling, crucial for viral replication.

Area of Science:

  • Virology
  • Molecular Biology
  • Pharmacology

Background:

  • Niclosamide is known to inhibit pH-dependent viruses by neutralizing endosomal acidity.
  • Niclosamide also disrupts the mTORC1 signaling pathway, which is essential for the replication of many viruses.

Purpose of the Study:

  • To investigate the inhibitory activity of niclosamide against HIV-1.
  • To determine if mTORC1 inhibition is involved in niclosamide's anti-HIV-1 activity.

Main Methods:

  • Cytotoxicity and anti-HIV-1 activity of niclosamide were assessed in TZM-bl and SupT1 cells.
  • The role of mTORC1 was explored using MHY1485, an mTORC1 activator, to reverse niclosamide-induced inhibition.
  • AMP-activated protein kinase (AMPK) activation and downstream substrate phosphorylation (S6K, 4E-BP1) were analyzed.

Main Results:

  • Niclosamide demonstrated dose- and time-dependent inhibition of HIV-1 replication, independent of reverse transcription and transcription.
  • Niclosamide downregulated mTORC1 via AMPK activation, decreasing S6K and 4E-BP1 phosphorylation and reducing HIV-1 p24 protein synthesis.
  • MHY1485 partially restored HIV-1 replication by increasing mTORC1 pathway phosphorylation and viral protein synthesis.

Conclusions:

  • Niclosamide's antiviral mechanism against HIV-1 operates through the AMPK-mTORC1 pathway.
  • This pathway represents a potential common therapeutic target for various viral infections.
Keywords:
AMPKBiomoleculesCell biologyHIV-1MicrobiologyMolecular biologyNiclosamideVirologymTORC1

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