This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pati, S. Articles by Reitz, M. Search for Related Content PubMed PubMed Citation Articles by Pati, S. Articles by Reitz, M.

 Previous Article  |  Next Article 

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

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-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). 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-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.

This article has been cited by other articles:

• Sin, S.-H., Roy, D., Wang, L., Staudt, M. R., Fakhari, F. D., Patel, D. D., Henry, D., Harrington, W. J. Jr, Damania, B. A., Dittmer, D. P. (2007). Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 109: 2165-2173 [Abstract] [Full Text]  
• Brinkmann, M. M., Pietrek, M., Dittrich-Breiholz, O., Kracht, M., Schulz, T. F. (2007). Modulation of Host Gene Expression by the K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus. J. Virol. 81: 42-58 [Abstract] [Full Text]  
• Caselli, E., Galvan, M., Cassai, E., Caruso, A., Sighinolfi, L., Di Luca, D. (2005). Human herpesvirus 8 enhances human immunodeficiency virus replication in acutely infected cells and induces reactivation in latently infected cells. Blood 106: 2790-2797 [Abstract] [Full Text]  
• Prakash, O., Swamy, O. R., Peng, X., Tang, Z.-Y., Li, L., Larson, J. E., Cohen, J. C., Gill, J., Farr, G., Wang, S., Samaniego, F. (2005). Activation of Src kinase Lyn by the Kaposi sarcoma-associated herpesvirus K1 protein: implications for lymphomagenesis. Blood 105: 3987-3994 [Abstract] [Full Text]  
• Montaner, S., Sodhi, A., Servitja, J.-M., Ramsdell, A. K., Barac, A., Sawai, E. T., Gutkind, J. S. (2004). The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 104: 2903-2911 [Abstract] [Full Text]  
• Guo, H.-G., Pati, S., Sadowska, M., Charurat, M., Reitz, M. (2004). Tumorigenesis by Human Herpesvirus 8 vGPCR Is Accelerated by Human Immuodeficiency Virus Type 1 Tat. J. Virol. 78: 9336-9342 [Abstract] [Full Text]  
• Staudt, M. R., Kanan, Y., Jeong, J. H., Papin, J. F., Hines-Boykin, R., Dittmer, D. P. (2004). The Tumor Microenvironment Controls Primary Effusion Lymphoma Growth in Vivo. Cancer Res. 64: 4790-4799 [Abstract] [Full Text]  
• Matta, H., Sun, Q., Moses, G., Chaudhary, P. M. (2003). Molecular Genetic Analysis of Human Herpes Virus 8-encoded Viral FLICE Inhibitory Protein-induced NF-{kappa}B Activation. J. Biol. Chem. 278: 52406-52411 [Abstract] [Full Text]