title: Vascular endothelial growth factor augments human herpesvirus-8 (HHV-8/KSHV) infection.
abstract: Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. The Raf oncoprotein enhances HHV-8 infection of target cells. In addition, we have previously demonstrated that Raf induces vascular endothelial growth factor (VEGF) expression. VEGF is a growth factor that has autocrine growth activity and has been implicated in the formation of the spindle shape cell morphology characteristic of Kaposi's sarcoma (KS). The aim of this study was to test the hypothesis that VEGF enhances infection of HHV-8. Herein, we demonstrate that the soluble VEGF enhanced green florescence protein encoding (GFP)-HHV-8 (rKSHV.152) infection of human foreskin fibroblasts (HFF) and not of 293 cells. We found this to be in part, due to the fact that HFF inherently produces significantly lower concentrations of VEGF when compared to 293 cells. Treating 293 cells (but not HFF) with a VEGF receptor (VEGFR) inhibitor significantly lowered infection. Furthermore, transfecting 293 cells with VEGF specific si-RNA did not alter the binding of HHV-8 to cells; but significantly lowered VEGF expression and thus GFP-HHV-8 infection. Interestingly, lowering VEGF expression in 293 cells wtih VEGF specific si-RNA did not completely inhibit GFP-HHV-8 infection. We conclude that VEGF is not a requirement for HHV-8 infection; but VEGF plays a major role in augmenting infection at a post binding stage of entry. These findings suggest that targeting VEGF/VEGFR may prove efficacious in controlling HHV-8 associated pathogenesis.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Ford
authors.forename: Khalief E
authors.initials: KE
authors.lastname: Hamden
authors.forename: Audy G
authors.initials: AG
authors.lastname: Whitman
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Shaw M
authors.initials: SM
authors.lastname: Akula
mesh_terms: D018929:Cell Culture Techniques; D005347:Fibroblasts; D006566:Herpesviridae Infections / Q000503:physiopathology*; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D007668:Kidney / Q000166:cytology; D012514:Sarcoma, Kaposi / Q000503:physiopathology* / Q000821:virology*; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D042461:Vascular Endothelial Growth Factor A