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Journal of Virology, September 2001, p. 8660-8673, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8660-8673.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Activation of NF-kappa B by the Human Herpesvirus 8 Chemokine Receptor ORF74: Evidence for a Paracrine Model of Kaposi's Sarcoma Pathogenesis

Shibani Pati,1,2 Marielle Cavrois,1 Hong-Guang Guo,1 James S. Foulke Jr.,1 Jynho Kim,2 Ricardo A. Feldman,2 and Marvin Reitz1,2,*

Institute of Human Virology, University of Maryland Biotechnology Institute,1 and Department of Microbiology and Immunology, University of Maryland,2 Baltimore, Maryland 21201

Received 11 January 2001/Accepted 1 June 2001

Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-kappa B independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-kappa B activation was enhanced by the chemokine GROalpha , but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GROalpha . ORF74 upregulated the expression of NF-kappa B-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-kappa B signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-kappa B and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.

* Corresponding author. Mailing address: Institute of Human Virology, University of Maryland, 725 W. Lombard St., Baltimore, MD 21201. Phone: (410) 708-4679. Fax: (410) 706-4694. E-mail: reitz{at}umbi.umd.edu.

Journal of Virology, September 2001, p. 8660-8673, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8660-8673.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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