The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

Abstract

We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein-coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Our lab and others have shown that transgenic expression of viral G protein-coupled receptor (vGPCR), the chemokine receptor encoded by HHV8 ORF74, induces development of angioproliferative lesions that resemble those seen in KS (9-11). In our model, the lesions are observed in ears, limbs, and tail and progress from erythematous lesions to nodules and tumors within 6 months (9). The lesions are composed of large numbers of spindleshaped CD34 + cells, vascular channels, and inflammatory cells. Conditional expression of vGPCR triggers expression of several angiogenic factors in lesional areas, and its inactivation results in regression of the angioproliferative lesions (12).

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

“…Among the HHV8 lytic genes, the ORF74, which encodes vGPCR can be expressed in the endothelial cell compartment where it provokes the apparition of KS-like lesions in mice (Montaner et al, 2003;Grisotto et al, 2006;Mutlu et al, 2007). However, the molecular mechanisms by which vGPCR alters endothelial homeostasis are not fully understood.…”

“…However, the ORF74 gene, which encodes a viral G-protein-coupled receptor (vGPCR), has the unique ability to recapitulate KS-like tumor progression when expressed in the endothelial cell compartment in mice models (Montaner et al, 2003;Grisotto et al, 2006;Mutlu et al, 2007). HHV8 vGPCR is a seven span transmembrane constitutively active receptor coupled to a heterotrimeric G protein, whose closest homologue is the chemokine receptor CXCR2 (Bais et al, 1998).…”

Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques

“…For real-time PCR analysis of chemokine receptors expressed by sorted monocyte subsets, previously described methods were used (50).…”

Chemokines in cancer related inflammation

“…HHV8 is the etiologic agent of Kaposi sarcoma and of hematological malignancies in humans; its genome encodes the constitutively active viral G-protein coupled receptor (vGPCR) which recognizes both ELR− and ELR + CXC chemokines. vGPCR acts as a transforming receptor in vitro and causes vascular lesions in transgenic mice, thus behaving as an oncogene [16]. Another example is the chemokine receptor US28 encoded by Cytomegalovirus; transgenic mice in which US28 expression was targeted to intestinal epithelial cells developed intestinal adenoma and carcinoma [17].…”