The herpes simplex virus-1 transactivator infected cell protein-4 drives VEGF-A dependent Neovascularization

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. © 2011 wuest et al.