Productive infection of HUVEC by HHV-8 is associated with changes compatible with angiogenic transformation

Abstract

Kaposi's Sarcoma (KS) is an angioproliferative disease associated with human herpesvirus 8 (HHV-8) infection. We have characterized the morphologic and phenotypic modifications of HUVEC in a model of productive HHV-8 infection. HHV-8 replication was associated with ultra-structural changes, flattened soma and a loss of marginal folds and intercellular contacts, and morphologic features, spindle cell conversion and cordon-like structures formation. Phenotypic changes observed on cordon-like structures included partial loss and redistribution of CD31/PECAM-1 and VE-cadherin, uPAR upregulation and de novo expression of CD13/APN. Such changes demonstrate the induction, in HUVEC, of an angiogenic profile. Most of these findings are directly linked to HHV-8-encoded proteins expression, suggesting that HHV-8 itself may participate to the initial steps of the angiogenic transformation in KS.

Kaposi's Sarcoma-Associated Herpesvirus Latent Gene vFLIP Inhibits Viral Lytic Replication through NF-κB-Mediated Suppression of the AP-1 Pathway: a Novel Mechanism of Virus Control of Latency

“…Such interplay of the two pathways in KSHV replication is perhaps best illustrated during primary infection with KSHV. While some studies have shown that the default KSHV replication pathway following primary infection in human foreskin fibroblasts and human dermal microvascular endothelial cells is latency (27), other studies have demonstrated active viral lytic replication at the early stage of KSHV primary infection (13,16,19), which correlates with the activation of the AP-1 pathway (42,58). It would be interesting to examine the relationship of KSHV replication programs with the status of the AP-1 and NF-B pathways during KSHV primary infection in different cell types.…”

Kaposi's Sarcoma-Associated Herpesvirus Disrupts Adherens Junctions and Increases Endothelial Permeability by Inducing Degradation of VE-Cadherin

“…In the following experiments, we focused our efforts on the early stage of KSHV infection. stage of KSHV infection (27,57,81,84). While some proinflammatory and proangiogenic cytokines have been shown to regulate endothelial permeability in some pathological conditions (21,33,34,47,65), confluent endothelial cells are usually refractory to these cytokines partly because of the growth contact-inhibition effect exerted by the adherens junctions (13,37,46,64).…”

“…Some members of matrix metalloproteinases (MMPs) also mediate vascular permeability induced by viral proteins or during viral infections (48,69). While KSHV infection of endothelial cells induces some of these proinflammatory and proangiogenic factors, as well as MMPs (14,27,54,57,66,67,76,81,82,84), conditioned medium from acute KSHV-infected endothelial monolayers that manifested the clear disruption of adherens junctions failed to induce the disruption of adherens junctions when added to uninfected confluent endothelial monolayers (Fig. 4C).…”

“…The disruption of adherens junctions mitigates contact inhibition and facilitates the growth of endothelial cells by transmitting mitogenic and survival signals, such as Src, phosphatidylinositol 3-kinase (PI 3-kinase), proteinase kinase C, protein kinase B, and mitogen-activated protein kinases (MAPKs), activated by extracellular growth and proangiogenic factors and by releasing ␤-catenin to the nucleus to promote the transcription of oncogenes, such as c-myc and cyclin D1 (15,71,74). We and others have shown that KSHV infection of endothelial cells activates many of these pathways and promotes the growth, angiogenesis, and invasion of the infected cells while simultaneously inducing proinflammatory and proangiogenic cytokines (14,27,54,57,66,67,76,81,82,84), which are consistent with the observed phenotypes of disruption of adherens junctions and increased endothelial permeability described in this study. Interestingly, these features are also characteristics of cellular transformation and the epithelial-to-mesenchymal transition of cancer cells (6,39).…”

The Viral Etiology of AIDS‐Associated Malignancies

“…Infection of primary endothelial cells by KSHV has been shown to lead to morphologic and phenotypic changes of these cells that resemble the characteristics of KS spindle cells, suggesting that KSHV can lead to malignant transformation and plays a role in the pathogenesis of KS (Flore et al, 1998;Foglieni et al, 2005;Moses et al, 1999). KSHV has been shown to encode for a number of viral genes that may contribute to tumorigenesis.…”