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Journal of Virology, May 2003, p. 5759-5773, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5759-5773.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Herpesvirus 8-Encoded vGPCR Activates Nuclear Factor of Activated T Cells and Collaborates with Human Immunodeficiency Virus Type 1 Tat

Shibani Pati,1 James S. Foulke Jr.,1 Oxana Barabitskaya,1 Jynho Kim,2 B. C. Nair,3 David Hone,1 Jennifer Smart,2 Ricardo A. Feldman,2 and Marvin Reitz1,2*

Institute of Human Virology, University of Maryland Biotechnology Institute,1 Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland 21201,2 Advanced BioScience Laboratory Inc., Kensington, Maryland 208953

Received 25 November 2002/ Accepted 11 February 2003

Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi's sarcoma (KS), encodes a chemokine receptor homologue, the viral G protein-coupled receptor (vGPCR), that has been implicated in KS pathogenesis. Expression of vGPCR constitutively activates several signaling pathways, including NF-{kappa}B, and induces the expression of proinflammatory and angiogenic factors, consistent with the inflammatory hyperproliferative nature of KS lesions. Here we show that vGPCR also constitutively activates the nuclear factor of activated T cells (NF-AT), another transcription factor important in regulation of the expression of inflammatory cytokines and related factors. NF-AT activation by vGPCR depended upon signaling through the phosphatidylinositol 3-kinase-Akt-glycogen synthetase kinase 3 (PI3-K/Akt/GSK-3) pathway and resulted in increased expression of NF-AT-dependent cell surface molecules (CD25, CD29, Fas ligand), proinflammatory cytokines (interleukin-2 [IL-2], IL-4), and proangiogenic factors (granulocyte-macrophage colony-stimulating factor GMCSF and TNF{alpha}). vGPCR expression also increased endothelial cell-T-cell adhesion. Although infection with HHV-8 is necessary to cause KS, coinfection with human immunodeficiency virus type 1 (HIV-1), in the absence of antiretroviral suppressive therapy, increases the risk of KS by many orders of magnitude. NF-AT and NF-{kappa}B activation by vGPCR was greatly increased by the HIV-1 Tat protein, although Tat alone had little effect on NF-AT. The enhancement of NF-AT by Tat appears to be mediated through collaborative stimulation of the PI3-K/Akt/GSK-3 pathway by vGPCR and Tat. Our data further support the idea that vGPCR contributes to the pathogenesis of KS by a paracrine mechanism and, in addition, provide the first evidence of collaboration between an HIV-1 protein and an HHV-8 protein.

* 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, May 2003, p. 5759-5773, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5759-5773.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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