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Arbovirus Infections As Screening Tools for the Identification of Viral Immunomodulators and Host Antiviral Factors
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Avermectins Inhibit Replication of Parvovirus B19 by Disrupting the Interaction Between Importin α and Non-Structural
Gualtiero Alvisi1, Elisabetta Manaresi2, Silvia Pavan1
1Department of Molecular Medicine, University of Padova, 35121 Padova, Italy.
Viruses
|February 26, 2025
Summary
Human parvovirus B19 (B19V) replication relies on NS1 protein nuclear import. Ivermectin and related avermectins inhibit this process, but toxicity limits their use, necessitating more specific B19V inhibitors.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Human parvovirus B19 (B19V) is a significant human pathogen.
- Viral replication occurs in erythroid progenitor cells (EPCs) via nuclear import of viral proteins, including non-structural protein 1 (NS1).
- The NS1 classical nuclear localization signal (cNLS) interacts with host importin-alpha (IMPα), presenting a potential antiviral target.
Purpose of the Study:
- To investigate the role of NS1 nuclear localization in B19V production.
- To evaluate the antiviral potential of ivermectin (IVM) and related avermectins (AVMs) against B19V.
- To identify selective inhibitors of the NS1-NLS:IMPα interaction.
Main Methods:
- Site-directed mutagenesis to create a K177T substitution in the B19V genome.
- In vitro assays to assess NS1-NLS:IMPα complex disruption by IVM and AVMs.
- Viral replication assays in UT7/EpoS1 cells and primary EPCs.
Main Results:
- NS1 nuclear localization is essential for B19V viability; K177T substitution yields a non-viable virus.
- IVM impairs the NS1-NLS:IMPα interaction and dose-dependently suppresses B19V replication in cell lines.
- Several AVMs, particularly Eprinomectin, inhibit B19V replication with nanomolar potency, but show reduced efficacy and toxicity in primary EPCs.
Conclusions:
- NS1 nuclear import is critical for B19V replication.
- IVM and AVMs show promise as B19V inhibitors by targeting the NS1-NLS:IMPα pathway.
- Further development of selective NS1-NLS:IMPα inhibitors is needed due to toxicity and limited efficacy in primary cells.
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