Dynasore disrupts trafficking of herpes simplex virus proteins.

Abstract

UNLABELLED:

Dynasore, a small-molecule inhibitor of the GTPase activity of dynamin, inhibits the entry of several viruses, including herpes simplex virus (HSV), but its impact on other steps in the viral life cycle has not been delineated. The current study was designed to test the hypothesis that dynamin is required for viral protein trafficking and thus has pleiotropic inhibitory effects on HSV infection. Dynasore inhibited HSV-1 and HSV-2 infection of human epithelial and neuronal cells, including primary genital tract cells and human fetal neurons and astrocytes. Similar results were obtained when cells were transfected with a plasmid expressing dominant negative dynamin. Kinetic studies demonstrated that dynasore reduced the number of viral capsids reaching the nuclear pore if added at the time of viral entry and that, when added as late as 8 h postentry, dynasore blocked the transport of newly synthesized viral proteins from the nucleus to the cytosol. Proximity ligation assays demonstrated that treatment with dynasore prevented the colocalization of VP5 and dynamin. This resulted in a reduction in the number of viral capsids isolated from sucrose gradients. Fewer capsids were observed by electron microscopy in dynasore-treated cells than in control-treated cells. There were also reductions in infectious progeny released into culture supernatants and in cell-to-cell spread. Together, these findings suggest that targeting dynamin-HSV interactions may provide a new strategy for HSV treatment and prevention.

IMPORTANCE:

HSV infections remain a global health problem associated with significant morbidity, particularly in neonates and immunocompromised hosts, highlighting the need for novel approaches to treatment and prevention. The current studies indicate that dynamin plays a role in multiple steps in the viral life cycle and provides a new target for antiviral therapy. Dynasore, a small-molecule inhibitor of dynamin, has pleiotropic effects on HSV-1 and HSV-2 infection and impedes viral entry, trafficking of viral proteins, and capsid formation.

• Authors: Mascha B Mues, Natalia Cheshenko, Duncan W Wilson, Leslie Gunther-Cummins, Betsy C Herold
• Journal: Journal of virology (J Virol) Vol. 89 Issue 13 Pg. 6673-84 (Jul 2015) ISSN: 1098-5514 [Electronic] United States
• PMID: 25878109 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Anti-Retroviral Agents
• Capsid Proteins
• Hydrazones
• N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
• VP5 protein, Herpes simplex virus type 1
• Viral Proteins
• Dynamins

Topics

• Anti-Retroviral Agents (metabolism)
• Capsid (metabolism)
• Capsid Proteins (metabolism)
• Cells, Cultured
• Centrifugation, Density Gradient
• Dynamins (metabolism)
• Epithelial Cells (virology)
• Herpesvirus 1, Human (physiology)
• Herpesvirus 2, Human (physiology)
• Humans
• Hydrazones (metabolism)
• Microscopy, Electron, Transmission
• Neurons (virology)
• Protein Transport (drug effects)
• Viral Proteins (metabolism)