Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This γ-herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the α3β1 surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This γ-herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the α3β1 surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm. Kaposi's sarcoma-associated herpesvirus (KSHV), 1The abbreviations used are: KSHV, Kaposi's sarcoma-associated herpesvirus; BSA, bovine serum albumin; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-related kinase; FAK, focal adhesion kinase; gB, glycoprotein B; GFP, green fluorescent protein; HIV, human immunodeficiency virus; HMVEC, human microvascular endothelial cell; KS, Kaposi's sarcoma; MAPK, mitogen-activated protein kinase; ORF, open reading frame; PBS, phosphate-buffered saline; PI, phosphatidylinositol; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. also known as human herpesvirus 8 (HHV-8), is the primary etiologic agent of Kaposi's sarcoma (KS), a neoplasm arising from endothelial cells. Viral DNA has been found in KS lesions from patients with all forms of the disease, namely AIDS-KS, classic KS, African endemic KS, and transplantation-associated KS. KS is most commonly found in the dermis but also occurs in viscera including lungs, liver, and intestines (1Antman K. Chang Y. N. Engl. J. Med. 2000; 342: 1027-1038Crossref PubMed Scopus (813) Google Scholar, 2Moore P.S. Chang Y. Annu. Rev. Microbiol. 2003; 57: 609-639Crossref PubMed Scopus (187) Google Scholar). The KSHV genome encodes over 85 genes, of which <10% are expressed during latent infection (3Russo J.J. Bohenzky R.A. Chien M.C. Chen J. Yan M. Maddalena D. Parry J.P. Peruzzi D. Edelman I.S. Chang Y. Moore P.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14862-14867Crossref PubMed Scopus (1313) Google Scholar, 4Sarid R. Flore O. Bohenzky R.A. Chang Y. Moore P.S. J. Virol. 1998; 72: 1005-1012Crossref PubMed Google Scholar). In KS tissues, KSHV infection is localized to KS spindle cells, the majority of which are latently infected. A small subpopulation, however, is lytically infected. Recent evidence suggests that both latency and lytic infection contribute importantly to KS pathogenesis (5Martin D.F. Kuppermann B.D. Wolitz R.A. Palestine A.G. Li H. Robinson C.A. N. Engl. J. Med. 1999; 340: 1063-1070Crossref PubMed Scopus (434) Google Scholar, 6Grundhoff A. Ganem D. J. Clin. Investig. 2004; 113: 124-136Crossref PubMed Scopus (292) Google Scholar, 7Glaunsinger B. Ganem D. Mol. Cell. 2004; 13: 713-723Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). KSHV encodes for several biologically active proteins, including the virion envelope-associated glycoprotein B (gB or ORF-8) (4Sarid R. Flore O. Bohenzky R.A. Chang Y. Moore P.S. J. Virol. 1998; 72: 1005-1012Crossref PubMed Google Scholar). Among the herpesvirus gB genes characterized to date, only the KSHV gB has the RGD (Arg-Gly-Asp) motif (amino acids 27–29), which is at the extracellular amino-terminal region after the putative signal sequence. This RGD sequence appears to be highly conserved among the KSHV strains analyzed from different geographical regions (8Meng Y.X. Spira T.J. Bhat G.J. Birch C.J. Cruce J.D. Edlin B.R. Edwards R. Gunthel R. Newton R. Stamey F.R. Wood C. Pellett P.E. Virology. 1999; 261: 106-119Crossref PubMed Scopus (98) Google Scholar). The RGD amino acids constitute the minimal region of several extracellular matrix proteins required for interaction with certain cell surface integrins. The RGD motif is the most common integrin recognition motif, but other RGD-independent integrin recognition motifs have also been reported (9Stone A.L. Kroeger M. Sang Q.X. J. Protein 1999; PubMed Scopus Google Scholar, K. C. S. D. Y. J. Full Text Full Text PDF PubMed Scopus Google Scholar). a gB has been in the glycoprotein B of the human of sequence A.L. H. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). 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This of virus activation of a endothelial receptor could contribute to the pathogenesis of KS. human microvascular endothelial cells from and in endothelial with green fluorescent protein cells a from of of is a of KSHV and virus human B cells. These cell as B. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. Virol. PubMed Scopus Google Scholar). human cells and cells with VEGFR-3 from and in with from VEGFR-3 from VEGFR-3 from A and from (VEGFR-3) and from and from growth factor receptor and from with a or VEGFR-3 for with PBS, cells with or to the cells and in the and cell cells with and in and and in for at cells with or for on with analyzed on a or used as J. Full Text Full Text PDF PubMed Scopus Google Scholar). to on to the A used as a to for as D. PubMed Scopus Google Scholar). 3 cells with PBS, in with for and as The to be green fluorescent cells a fluorescent and DNA cells to a of with at and for the cells at for The and at for The in growth with and at for The used for virus and B. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. Virol. PubMed Scopus Google Scholar). to the DNA from KSHV the The and the KSHV have been C. B. J. Virol. 2004; PubMed Scopus Google Scholar). The used to and the a reported C. S. B. 2004; PubMed Scopus Google Scholar). The used to a and the of DNA in the cells to KSHV with a of infection of DNA cell for or The cells in the with as the cells, and as and KSHV and a gB which is that an sequence of have been N. B. J. Virol. 2003; PubMed Scopus Google Scholar, B. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). for in inhibit cells for with and with or as cell and used for the and as J. 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KSHV or KSHV to the cells the VEGF used as a with BSA, cells with and the of the or in a The of the proteins in with The of with for at The with for at with migration with and the the cells. from with with and with migration with and or with for at and the of the The to of migration in the or of or The at in and for 3 cells from the the surface with a and the cells on the surface and with The of cells in cells found in the the The migration the of cells in to the of cells. with and with and with with The cells with or for at and at in the or of or as and to for the cell to the Viral and cells or with in at for 3 and and at for 3 with growth KSHV at a of infection of KSHV fluorescent cells a fluorescent or in and analyzed on a green fluorescent cells cells with and with the and the in the of cells. to KSHV or and in the of or in for the this analyzed and for and the and the human to the and has been at and or are in the of and are with the VEGFR-3 or with of cells and with or for cell on The of with an The with an The of with The with as as gB with to to of to cells KSHV or to cells, and the of to the cell surface of to cells KSHV KSHV KSHV or VEGF to cells, and the of to the cell surface are the of in with in cells or with in cells for the cell with The on and to with and as cell migration and are of VEGFR-3 or integrin KSHV cell migration is with the or with for at migration in to or for 3 The cells and The migration the of cells in to the of cells in the which and growth of integrin KSHV with or for at migration in to or for 3 The cells and The migration as of VEGFR-3 KSHV endothelial cell proliferation. with the or for at in in with in the or of or for the cell The the of in as with the of KSHV cells or cells and and or or with in at for 3 and and at for 3 with growth cells a fluorescent or in and analyzed on a as an of and the green fluorescent cells a fluorescent cells with and with and are The all treatment The from and are as in and as with the cells or the VEGFR-3 cells and of VEGFR-3 KSHV infection and KSHV-mediated transformation. 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