Binding of Herpes Simplex Virus Type-1 Virions Leads to the Induction of Intracellular Signalling in the Absence of Virus Entry

Iain J Macleod,Tony Minson,Ding Xiang Liu

doi:10.1371/journal.pone.0009560

Iain J Macleod, Tony Minson + Show 1 more

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https://doi.org/10.1371/journal.pone.0009560

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Journal: PloS one	Publication Date: Mar 5, 2010
Citations: 74	License type: CC BY 4.0

Affiliation: University of Cambridge

Abstract

The envelope of HSV-1 contains a number of glycoproteins, four of which are essential for virus entry. Virus particles lacking gB, gD, gH or gL are entry-defective, although these viruses retain the ability to bind to the plasma membrane via the remaining glycoproteins. Soluble forms of gD have been shown to trigger the nuclear translocation of the NF-κB transcriptional complex in addition to stimulating the production of Type I interferon. By taking advantage of the entry-defective phenotype of glycoprotein-deficient HSV-1 virus particles, the results presented here show that binding of virions to cellular receptors on the plasma membrane is sufficient to stimulate a change in cellular gene expression. Preliminary microarray studies, validated by quantitative real-time PCR, identified the differential expression of cellular genes associated with the NF-κB, PI3K/Akt, Jak/Stat and related Jak/Src pathways by virions lacking gB or gH but not gD. Gene induction occurred at a few particles per cell, corresponding to physiological conditions during primary infection. Reporter assay studies determined that NF-κB transcriptional activity is stimulated within an hour of HSV-1 binding, peaks between two and three hours post-binding and declines to background levels by five hours after induction. The immediate, transient nature of these signalling events suggests that HSV-1 glycoproteins, particularly gD, may alter the cellular environment pre-entry so as to condition the cell for viral replication.

Highlights

Subjugation of the intracellular environment by viruses is essential to ensure the effective expression and replication of the viral genome to allow production of progeny virions
Binding of HSV-1 to permissive cells occurs through viral glycoproteins on the viral envelope interacting with specific receptors on the cell surface, triggering fusion of the plasma membrane with the outer envelope
Serum-starved Human foreskin fibroblast cells (HFF) were inoculated with 1000 particles/cell of DgB, DgD or DgH entry-defective HSV-1 virions

Summary

Introduction

Subjugation of the intracellular environment by viruses is essential to ensure the effective expression and replication of the viral genome to allow production of progeny virions One such viral strategy involves hijacking signalling pathways that control host gene transcription. Binding of HSV-1 to permissive cells occurs through viral glycoproteins on the viral envelope interacting with specific receptors on the cell surface, triggering fusion of the plasma membrane with the outer envelope. Five of these glycoproteins are known to be involved in virion binding to the cell surface: gB, gC, gD and the heterodimer gH-L. Only gC is dispensable for allowing productive infection as deletion of gB, gD or gH-L results in an entry-defective phenotype [2][3]. gD is known to bind independently to HvEM, nectin-1 and nectin-2, whereas gH interacts with the avb integrin, with the paired immunoglobulin-like receptor, PILRa, acting as a receptor for gB [2][4][5]

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