Abstract
Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for virus infectivity and binds to a cellular receptor, insulin-degrading enzyme (IDE), through its unique amino terminal extracellular domain. Previous work has shown IDE plays an important role in VZV infection and virus cell-to-cell spread, which is the sole route for VZV spread in vitro. Here we report that a recombinant soluble IDE (rIDE) enhances VZV infectivity at an early step of infection associated with an increase in virus internalization, and increases cell-to-cell spread. VZV mutants lacking the IDE binding domain of gE were impaired for syncytia formation and membrane fusion. Pre-treatment of cell-free VZV with rIDE markedly enhanced the stability of the virus over a range of conditions. rIDE interacted with gE to elicit a conformational change in gE and rendered it more susceptible to proteolysis. Co-incubation of rIDE with gE modified the size of gE. We propose that the conformational change in gE elicited by IDE enhances infectivity and stability of the virus and leads to increased fusogenicity during VZV infection. The ability of rIDE to enhance infectivity of cell-free VZV over a wide range of incubation times and temperatures suggests that rIDE may be useful for increasing the stability of varicella or zoster vaccines.
Highlights
Varicella-zoster virus (VZV), a member of the alpha-herpesvirus family, is the etiologic agent of chickenpox and shingles
We have shown that soluble recombinant soluble IDE (rIDE) enhances VZV infectivity and cell-to-cell spread in human melanoma cells at an early step of virus infection. rIDE interacted with glycoprotein E (gE) to elicit a conformational change in gE and modified the size of gE
A VZV mutant virus lacking the insulin-degrading enzyme (IDE) binding domain of gE was impaired for syncytia formation and membrane fusion, suggesting that IDE enhances infectivity and stability of the virus through eliciting a conformational change in gE and modulating fusogenicity during VZV infection
Summary
Varicella-zoster virus (VZV), a member of the alpha-herpesvirus family, is the etiologic agent of chickenpox and shingles. Previous studies have identified cellular molecules that are important for entry of VZV into cells. Previous studies from our laboratory showed that insulin-degrading enzyme (IDE), a member of the zinc metalloproteinase family, is a putative cellular receptor for VZV [3]. VZV glycoprotein E (gE), which is essential for virus infectivity [4,5], interacts with IDE through a binding domain located at the amino terminus of the ectodomain of gE that is not conserved in other human herpesviruses [3,6,7,8]. VZV deleted for the IDE binding domain in gE is impaired for infectivity of cell-free virus [5] and shows reduced cell-to-cell spread of virus both in vitro and in human skin xenografts in SCID mice [5,8]. We show that the interaction of IDE with gE is important for VZV-induced syncytia formation and fusogenicity, and that recombinant soluble IDE (rIDE) modifies gE, induces a conformation change in gE, enhances VZV infectivity, and stabilizes cell-free virus
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