Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly

J Biochem. 2018 Dec 1;164(6):397-406. doi: 10.1093/jb/mvy066.

Abstract

Heat shock protein 90 (Hsp90) has been identified as an essential host factor for the infection and replication of several viruses, including HSV-1. Recent works have clearly shown that Hsp90 plays a role in the early stages of HSV-1 infection, including nuclear import and DNA replication. However, the role of Hsp90 in the late stages of HSV-1 infection remains unclear. In this study, we found that Hsp90 was up-regulated during late viral infection. Treatment with the Hsp90 inhibitor AT-533 significantly decreased the intracellular and extracellular virus titers, and strongly inhibited nucleocapsid egress from the nucleus. More detailed studies revealed that AT-533 inhibited the nuclear egress of the viral nucleocapsid by suppressing the expression and translocation of nuclear-associated proteins pUL31 and pUL34. In addition, we found that AT-533 hindered the assembly of virus particles possibly though affecting the localization of glycoproteins in the endoplasmic reticulum and Golgi apparatus. These results thus invoke a new role for Hsp90 in the nucleocapsid egress and viral maturation of HSV-1, and further promote the development of Hsp90 inhibitors as potential anti-HSV-1 drugs.

Publication types

  • Comparative Study

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology*
  • Benzamides / adverse effects
  • Benzamides / pharmacology*
  • Benzoquinones / adverse effects
  • Benzoquinones / pharmacology
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cell Nucleus / virology
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Cytopathogenic Effect, Viral / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation, Viral / drug effects
  • Green Fluorescent Proteins / chemistry
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Herpesvirus 1, Human / drug effects*
  • Herpesvirus 1, Human / physiology
  • Herpesvirus 1, Human / ultrastructure
  • Kinetics
  • Lactams, Macrocyclic / adverse effects
  • Lactams, Macrocyclic / pharmacology
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Vero Cells
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Assembly / drug effects*

Substances

  • Antiviral Agents
  • Benzamides
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • UL31 protein, Human herpesvirus 1
  • UL34 protein, Human herpesvirus 1
  • Viral Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • tanespimycin