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Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB

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Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-κB2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-κB2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-κB2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2.

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Acknowledgments

We thank William W. Hall and Hiroyuki Miyoshi for providing Tax2B plasmid and lentiviral expression vector, respectively. We also wish to thank Misako Tobimatsu for her technical assistance. This study was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Authors’ contributions

YM and MT performed most of the analysis and wrote the manuscript. TT and MH constructed the Tax mutant constructs and performed the initial experiments indicating that Tax1 but not Tax1/225-232 interacts with p100/p52. TH and MM provided information for the OX40L promoter and its regulation by Tax1 and Tax2. YA and ST contributed to the data interpretation. YT provided the anti-Tax and anti-OX40L antibodies. MF contributed to the conception and design of the study and the data interpretation and wrote and drafted the manuscript. All authors read and approved the final manuscript.

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    Authors and Affiliations

    1. Divisions of Virology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata, 951-8510, Japan

      Yosuke Motai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara & Masahiro Fujii

    2. Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

      Yosuke Motai, Yutaka Aoyagi & Shuji Terai

    3. Division of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

      Takayuki Takachi

    4. Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan

      Mariko Mizuguchi

    5. Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan

      Yuetsu Tanaka

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    1. Yosuke Motai
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    Yosuke Motai and Masahiko Takahashi have contributed equally to this study.

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    Motai, Y., Takahashi, M., Takachi, T. et al. Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB. Virus Genes 52, 4–13 (2016). https://doi.org/10.1007/s11262-015-1277-7

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