Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Binding of Herpes Simplex Virus Type-1 Virions Leads to the Induction of Intracellular Signalling in the Absence of Virus Entry 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. 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 ultimately control host gene transcription. Interactions between intracellular viral proteins and cellular kinases responsible for signal transduction are a means by which to achieve this. However, there is growing evidence to support the premise that glycoproteins on the surface of virus particles may trigger intracellular signalling pathways by interacting with their cognate receptors on the host cell membrane [1] .