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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zoeteweij, J. P. Articles by Blauvelt, A. Search for Related Content PubMed PubMed Citation Articles by Zoeteweij, J. P. Articles by Blauvelt, A. Related Collections Immunobiology Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2001, Vol. 97, No. 8, pp. 2374-2380 IMMUNOBIOLOGY Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus J. Paul Zoeteweij, Ashlee V. Moses, Andrea S. Rinderknecht, David A. Davis, Willem W. Overwijk, Robert Yarchoan, Jan M. Orenstein, and Andrew Blauvelt From the Dermatology Branch, the HIV and AIDS Malignancy Branch, and the Surgery Branch, National Cancer Institute, Bethesda, MD; the Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR; and the Pathology Department, George Washington University, Washington, DC. Kaposi sarcoma-associated herpesvirus (KSHV) is associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman disease. Reactivation of KSHV in latently infected cells and subsequent plasma viremia occur before the development of KS. Intracellular signaling pathways involved in KSHV reactivation were studied. In latently infected PEL cells (BCBL-1), KSHV reactivation in single cells was determined by quantitative flow cytometry. Viral particle production was determined by electron microscope analyses and detection of minor capsid protein in culture supernatants. Agents that mobilized intracellular calcium (ionomycin, thapsigargin) induced expression of KSHV lytic cycle-associated proteins and led to increased virus production. Calcium-mediated virus reactivation was blocked by specific inhibitors of calcineurin-dependent signal transduction (cyclosporine, FK506). Similarly, calcium-mediated virus reactivation in KSHV-infected dermal microvascular endothelial cells was blocked by cyclosporine. Furthermore, retroviral transduction with plasmid DNA encoding VIVIT, a peptide specifically blocking calcineurin-NFAT interactions, inhibited calcium-dependent KSHV reactivation. By contrast, chemical induction of lytic-phase infection by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate was blocked by protein kinase C inhibitors, but not by calcineurin inhibitors. In summary, calcineurin-dependent signal transduction, an important signaling cascade in vivo, induces calcium-dependent KSHV replication, providing a possible target for the design of antiherpesvirus strategies in KSHV-infected patients. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. M. Brinkmann, M. Pietrek, O. Dittrich-Breiholz, M. Kracht, and T. F. Schulz Modulation of Host Gene Expression by the K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus J. Virol., January 1, 2007; 81(1): 42 - 58. [Abstract] [Full Text] [PDF] B. C. Gilger, J. H. Salmon, D. A. Wilkie, L. P. J. Cruysberg, J. Kim, M. Hayat, H. Kim, S. Kim, P. Yuan, S. S. Lee, et al. A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2596 - 2605. [Abstract] [Full Text] [PDF] A. Cohen, C. Brodie, and R. 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	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020