Kaposi's Sarcoma-Associated Herpesvirus Downregulates Transforming Growth Factor beta 2 To Promote Enhanced Stability of Capillary-Like Tube Formation

• Published in: Journal of virology 2014-12, Vol.88 (24), p.14301-14309
• Main Authors: DiMaio, Terri A, Gutierrez, Kimberley D, Lagunoff, Michael
• Format: Article
• Language: English
• Subjects: Human herpesvirus 8; Kaposi's sarcoma-associated herpesvirus
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01696-14

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), the most common tumor of AIDS patients worldwide. A key characteristic of KS tumors is extremely high levels of vascular slits and extravasated red blood cells, making neoangiogenesis a key component of the tumor. The main KS tumor cell is the spindle cell, a cell of endothelial origin that maintains KSHV predominantly in the latent state. In cultured endothelial cells, latent KSHV infection induces angiogenic phenotypes, including longer-term stabilization of capillary-like tube formation in Matrigel, a basement membrane matrix. The present studies show that KSHV infection of endothelial cells strongly downregulates transforming growth factor beta 2 (TGF- beta 2). This downregulation allows the stabilization of capillary-like tube formation during latent infection, as the addition of exogenous TGF- beta 2 inhibits the KSHV-induced stability of these structures. While two KSHV microRNAs are sufficient to downregulate TGF- beta 2 in endothelial cells, they are not required during KSHV infection. However, activation of the gp130 cell surface receptor is both necessary and sufficient for downregulation of TGF- beta 2 in KSHV-infected cells. IMPORTANCE Kaposi's sarcoma is a highly vascularized, endothelial cell-based tumor supporting large amounts of angiogenesis. There is evidence that KSHV, the etiologic agent of KS, induces aberrant angiogenesis. For example, KSHV induces stabilization of capillary-like tube formation in cultured endothelial cells. A clearer understanding of how KSHV regulates angiogenesis could provide potential therapeutic targets for KS. We found that KSHV downregulates TGF- beta 2, a cytokine related to TGF- beta 1 that is known to inhibit angiogenesis. The downregulation of this inhibitor promotes the stability of capillary-like tube formation insofar as adding back TGF- beta 2 to infected cells blocks KSHV-induced long-term tubule stability. Therefore, KSHV downregulation of TGF- beta 2 may increase aberrant vascularization in KS tumors through increased capillary formation and thereby aid in KS tumor promotion.