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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 p12I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells

Wei Ding,1 Björn Albrecht,1,{dagger} Robert E. Kelley,2 Natarajan Muthusamy,3,4,5 Seung-Jae Kim,1 Ruth A. Altschuld,2 and Michael D. Lairmore1,4,5*

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, p12I and p27I, is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12I 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 p12I may modulate calcium release from the ER. Here, we report that p12I expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12I-mediated NFAT activation independently of its ability to bind p12I. 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 p12I-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12I 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.

* Corresponding author. Mailing address: Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Rd., Columbus, OH 43210. Phone: (614) 292-4489. Fax: (614) 292-6473. E-mail: Lairmore.1{at}osu.edu.

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

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.



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