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Abstract
Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) are two closely related human alphaherpesviruses that persistently infect most adults worldwide and cause a variety of clinically important diseases. Herpesviruses are extremely well adapted to their hosts and interact broadly with cellular proteins to regulate virus replication and spread. However, it is incompletely understood how HSV-1 and VZV interact with the host proteome during productive infection. This study determined the temporal changes in virus and host protein expression during productive HSV-1 and VZV infection in the same cell type. Results demonstrated the temporally coordinated expression of HSV-1 and VZV proteins in infected cells. Analysis of the host proteomes showed that both viruses affected extracellular matrix composition, transcription, RNA processing and cell division. Moreover, the prominent role of epidermal growth factor receptor (EGFR) signaling during productive HSV-1 and VZV infection was identified. Stimulation and inhibition of EGFR leads to increased and decreased virus replication, respectively. Collectively, the comparative temporal analysis of viral and host proteomes in productively HSV-1 and VZV-infected cells provides a valuable resource for future studies aimed to identify target(s) for antiviral therapy development.
Highlights
Most adults worldwide are infected with the human alpha-herpesviruses herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) (Arvin and Gilden, 2013; Roizman et al, 2013)
Antibodies used for western blotting (WB): mouse anti-VZV ORF4, ORF8, ORF31 (clone 31c.09, ORF36 and ORF63 (Lenac Roviš et al, 2013), rabbit polyclonal anti-Green fluorescent protein (GFP) (A11122) and mouse anti-SPARC, mouse anti-β-actin, mouse anti-PLAA, mouse anti-NLRP14 and mouse anti-lysine 6-oxidase (LOX), mouse anti-epidermal growth factor receptor (EGFR) and rabbit anti-phospho-EGFR (Tyr1068), mouse antiHSV-1 ICP0, mouse anti-ICP4 and mouse anti-glycoprotein D all provided by the University of Glasgow (United Kingdom), rabbit anti-US1 (ICP22) polyclonal antibody R77, mouse anti-UL29 (ICP8), IRDye 680- and IRDye 800-conjugated goat anti-rabbit and goat anti-mouse antibodies (Westburg)
In total 51 of 73 (70%) canonical HSV-1 proteins included in the UniProt database (The Uniprot Consortium, 2017) were consistently detected in three independent experiments (Supplementary Table S1)
Summary
Most adults worldwide are infected with the human alpha-herpesviruses (αHHV) herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) (Arvin and Gilden, 2013; Roizman et al, 2013). Both viruses are typically acquired during childhood and subsequently establish a lifelong latent infection in sensory neurons. VZV causes varicella (chickenpox) as a primary infection and herpes zoster (HZ; shingles) upon reactivation from latency, frequently complicated by chronic pain (post-herpetic neuralgia) (Arvin and Gilden, 2013). Insight into fundamental biological processes shared by HSV1 and VZV could provide valuable target(s) to develop novel antiviral therapies
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