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.

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

“…Neovascularization can be further separated into hemangiogenesis (development of blood vessels) and lymphangiogensis (development of lymphatic vessels). In HSK, the normally avascular cornea begins to express proangiogenic growth factors, such as VEGF-A/C/D, in response to inflammation, with lymphangiogenesis developing as soon as 1 day postinfection in mice (5)(6)(7). VEGF-A appears to be of particular importance, as it is the only VEGF isoform yet tested that induces both hemangiogenesis and lymphangiogenesis (7,8).…”

“…In HSK, the normally avascular cornea begins to express proangiogenic growth factors, such as VEGF-A/C/D, in response to inflammation, with lymphangiogenesis developing as soon as 1 day postinfection in mice (5)(6)(7). VEGF-A appears to be of particular importance, as it is the only VEGF isoform yet tested that induces both hemangiogenesis and lymphangiogenesis (7,8). The levels of VEGF in the eye following HSV-1 infection are increased by a reduction in the amount of soluble VEGF receptor 1 (sVEGFR-1), as well as in-creased levels of VEGF produced by infected epithelial cells and surrounding uninfected cells (driven by interleukin-17A [IL-17A]) (9,10).…”

“…The levels of VEGF in the eye following HSV-1 infection are increased by a reduction in the amount of soluble VEGF receptor 1 (sVEGFR-1), as well as in-creased levels of VEGF produced by infected epithelial cells and surrounding uninfected cells (driven by interleukin-17A [IL-17A]) (9,10). In HSV-1 ocular infection, VEGF-A expression is directly stimulated by the ICP4 immediate-early transactivator (7). The ICP4 protein activates VEGF-A transcription by binding the proximal VEGF-A gene promoter.…”

Tumor Necrosis Factor Alpha and Interleukin-6 Facilitate Corneal Lymphangiogenesis in Response to Herpes Simplex Virus 1 Infection

“…Recent studies have investigated the mechanisms by which HSV-1 induces lymphangiogenesis in the cornea during early acute infection (10,11). Following HSV-1 infection of corneal epithelial cells, the HSV-1-encoded transcription factor ICP4 binds the promoter region of VEGFA and drives expression of the proangiogenic growth factor (11).…”

“…Following HSV-1 infection of corneal epithelial cells, the HSV-1-encoded transcription factor ICP4 binds the promoter region of VEGFA and drives expression of the proangiogenic growth factor (11). This leads to extensive lymphangiogenesis in the corneal tissue (10,11).…”