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Journal of Virology, October 2002, p. 10374-10382, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10374-10382.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human T-Cell Lymphotropic Virus Type 1 p12^I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells

Wei Ding,¹ Björn Albrecht,^1, Robert E. Kelley,² Natarajan Muthusamy,^3,4,5 Seung-Jae Kim,¹ Ruth A. Altschuld,² and Michael D. Lairmore^1,4,5*

Center for Retrovirus Research and Department of Veterinary Biosciences,¹ Department of Molecular and Cellular Biochemistry, College of Medicine and Public Health,² Department of Pediatrics,³ Comprehensive Cancer Center, The Arthur G. James Cancer Hospital and Solove Research Institute,⁴ Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210⁵

Received 13 March 2002/ Accepted 28 June 2002

Human T-cell lymphotropic virus type 1 (HTLV-1) establishes persistent infection and is associated with lymphoproliferative or neurodegenerative diseases. As a complex retrovirus, HTLV-1 contains typical structural and enzymatic genes, as well as regulatory and accessory genes encoded in the pX region. The early events necessary for HTLV-1 to establish infection in lymphocytes, its primary target cells, remain unresolved. Recent studies have demonstrated the importance of regulatory and accessory gene products in determining this virus-host interaction. Among these, pX open reading frame I, which encodes two proteins, p12^I and p27^I, is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12^I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12^I expression induces the calcium-responsive T-cell transcription factor, nuclear factor of activated T cells (NFAT), in the presence of phorbol ester activation. Based on these studies, we hypothesize that p12^I may modulate calcium release from the ER. Here, we report that p12^I expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12^I-mediated NFAT activation independently of its ability to bind p12^I. Chemical inhibition studies using inhibitors of inositol 1,4,5-triphosphate receptor and calcium release-activated calcium channels suggest that inositol 1,4,5-triphosphate receptor in the ER membrane and calcium release-activated calcium channels in the plasma membrane contribute to p12^I-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12^I in elevating cytoplasmic calcium, an antecedent to T-cell activation, and further support the important role of this accessory protein in the early events of HTLV-1 infection.

Present address: Howard Hughes Medical Institute, Molecular Pathogenesis Program, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016.

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