title: The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent neovascularization.
abstract: Herpes simplex virus-1 (HSV-1) causes lifelong infection affecting between 50 and 90% of the global population. In addition to causing dermal lesions, HSV-1 is a leading cause of blindness resulting from recurrent corneal infection. Corneal disease is characterized by loss of corneal immunologic privilege and extensive neovascularization driven by vascular endothelial growth factor-A (VEGF-A). In the current study, we identify HSV-1 infected cells as the dominant source of VEGF-A during acute infection, and VEGF-A transcription did not require TLR signaling or MAP kinase activation. Rather than being an innate response to the pathogen, VEGF-A transcription was directly activated by the HSV-1 encoded immediate early transcription factor, ICP4. ICP4 bound the proximal human VEGF-A promoter and was sufficient to promote transcription. Transcriptional activation also required cis GC-box elements common to the VEGF-A promoter and HSV-1 early genes. Our results suggest that the neovascularization characteristic of ocular HSV-1 disease is a direct result of HSV-1's major transcriptional regulator, ICP4, and similarities between the VEGF-A promoter and those of HSV-1 early genes.
authors: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors: Todd
authors: T
authors: Wuest
authors: Min
authors: M
authors: Zheng
authors: Stacey
authors: S
authors: Efstathiou
authors: William P
authors: WP
authors: Halford
authors: Daniel J J
authors: DJ
authors: Carr
mesh_terms: D000818:Animals; D002460:Cell Line; D005123:Eye / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D016849:Keratitis, Herpetic / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D009389:Neovascularization, Pathologic / Q000235:genetics; D010957:Plasmids; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C048925:herpes simplex virus, type 1 protein ICP4