KSHV promotes leukocyte adhesion and transendothelial migration via induction of VCAM1

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are gammaherpesviruses associated with multiple human cancers. Kaposi's sarcoma (KS) is a human malignancy associated with KSHV infection. KS lesions are characterized by proliferating endothelial-derived spindle cells, leaky blood vessels, and inflammatory infiltrating leukocytes. The inflammatory leukocytes secrete cytokines and growth factors that may contribute to the survival and proliferation of tumor cells. Unless exposed to inflammatory cytokines, resting endothelial cells usually do not express adhesion molecules. Here, we identify a novel mechanistic link demonstrating that KSHV-infected latent endothelial cells express vascular cell adhesion molecule (VCAM1) and induce leukocyte adhesion and transendothelial migration (TEM) in a VCAM1-dependent manner. Inhibition of VCAM1 function using siRNA knockdown or antibody blockade impairs leukocyte adhesion and TEM, suggesting that cell adhesion and TEM are mediated by VCAM1. VCAM1 expression in KSHV-infected endothelial cells involves the non-canonical NF-кB (NF-κB2) pathway because depletion of NIK, IKKα, RelB, or NF-κB p52 via siRNA results in a decrease of VCAM1 levels, as well as a corresponding impairment of cell adhesion and TEM. Thus, KSHV-infected endothelial cells likely promote the infiltration of immune cells by modulating the expression of adhesion factors like VCAM1 on their surface. Moreover, we report that KSHV vFLIP, a latency protein encoded by the virus, directly induces VCAM1 expression and promotes leukocyte adhesion and transendothelial migration. We further demonstrate that endothelial cells infected with a vFLIP-deleted virus had reduced VCAM1 expression and reduced leukocyte adhesion and transendothelial migration.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is associated with the development of Kaposi's sarcoma (KS). KS tumors are characterized by proliferating endothelial-derived spindle cells and infiltrating leukocytes, which secrete cytokines and growth factors that may contribute to the proliferation of tumor cells. Unless exposed to inflammatory cytokines, resting endothelial cells usually do not express adhesion molecules. Here, we demonstrate that KSHV-infected latent endothelial cells induce the expression of vascular cell adhesion molecule, which promotes leukocyte adhesion and transendothelial migration.