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Journal of Virology, August 2005, p. 9449-9457, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9449-9457.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis

Hajime Hiraragi,1 Bindhu Michael,1,{dagger} Amrithraj Nair,1,{dagger} Micol Silic-Benussi,2 Vincenzo Ciminale,2 and Michael Lairmore1,3,4*

Center for Retrovirus Research and Department of Veterinary Biosciences, College of Veterinary Medicine,1 Comprehensive Cancer Center,3 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio,4 Department of Oncology and Surgical Sciences, University of Padova, Padua 35128, Italy2

Received 7 October 2004/ Accepted 18 April 2005

Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia. In addition to typical retroviral structural and enzymatic gene products, HTLV-1 encodes unique regulatory and accessory proteins, including a singly spliced pX open reading frame II (ORF II) product, p13II. We have demonstrated that proviral clones of HTLV-1 which are mutated in pX ORF II fail to obtain typical proviral loads and antibody responses in a rabbit animal model. p13II localizes to mitochondria and reduces cell growth and tumorigenicity in mice, but its function in human lymphocytes remains undetermined. For this study, we analyzed the functional properties of Jurkat T cells expressing p13II, using both transient and stable expression vectors. Our data indicate that p13II-expressing Jurkat T cells are sensitive to caspase-dependent, ceramide- and FasL-induced apoptosis. p13II-expressing Jurkat T cells also exhibited reduced proliferation when cultured at a high density. Furthermore, preincubation of the p13II-expressing cells with a farnesyl transferase inhibitor, which blocks the posttranslational modification of Ras, markedly reduced FasL-induced apoptosis, indicating the participation of the Ras pathway in p13II's influence on lymphocyte survival. Our data are the first to demonstrate that p13II alters Ras-mediated apoptosis in T lymphocytes, and they reveal a potential mechanism by which HTLV-1 alters lymphocyte proliferation.

* Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210. Phone: (614) 292-4489. Fax: (614) 292-6473. E-mail: lairmore.1{at}osu.edu.

{dagger} Present address: Merck Research Laboratories, Merck & Co., Inc., Sumneytown Pike, P.O. Box 4, West Point, PA 19486-0004.

Journal of Virology, August 2005, p. 9449-9457, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9449-9457.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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