the herpes simplex virus-1 transactivator infected cell protein-4 drives vegf-a dependent neovascularization单纯疱疹的virus-1反式激活因子感染细胞含有驱动器vegf-a依赖新血管形成.pdfVIP

The Herpes Simplex Virus-1 Transactivator Infected Cell Protein-4 Drives VEGF-A Dependent Neovascularization 1,2 2 3 4 1,2 Todd Wuest , Min Zheng , Stacey Efstathiou , William P. Halford , Daniel J. J. Carr * 1 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America, 2 Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America, 3 Department of Pathology, University of Cambridge, Cambridge, United Kingdom, 4 Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America 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 sugg