HTLV-1 infection to hematopoietic stem cells

• Project/Area Number: 17K19610
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Matsuoka Masao 熊本大学, 大学院生命科学研究部(医), 教授 (10244138)
• Co-Investigator(Kenkyū-buntansha): 安永 純一朗 京都大学, ウイルス・再生医科学研究所, 講師 (40362404)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: HTLV-1 / Tax / 血液幹細胞 / 成人T細胞白血病 / HTLV-1関連脊髄症 / ヒトT細胞白血病ウイルス1型 / レトロウイルス / 潜伏感染 / 樹状細胞 / リザーバー

Outline of Final Research Achievements

HTLV-1 infects mainly CD4+ T cells in vivo. However, its receptor is glucose transporter 1 (GLUT-1). We found the same integration sites in the different hematopoietic cells, indicating that HTLV-1 infects hematopoietic stem cells. The proportion of infected CD4+ T cells with identical integration sites is 16-35%. More than half of Infected neutrophils exist over one year. Presence of HTLV-1 infected hematopoietic stem cells is possibly the basis for leukemogenesis by HTLV-1.

Academic Significance and Societal Importance of the Research Achievements

HTLV-1の血液幹細胞への感染は否定されてきたが、今回の研究はこれを証明し、HTLV-1の感染拡大様式に新たな知見をもたらした。我々の研究を発表した後にATL患者で同じHTLV-1プロウイルス組み込み部位を有しているが異なるT細胞受容体再構成を有する症例が複数報告された。HTLV-1が感染した未熟な細胞が白血病となっていることを示しており、我々の研究はATLの発症機構に新たな展開をもたらす知見である。

Research Products

• [Int'l Joint Research] Imperial College London(英国)
• [Int'l Joint Research] Imperial College London(英国)
• [Int'l Joint Research] Imperial College London(英国)
• [Journal Article] IL-2/IL-2 Receptor Pathway Plays a Crucial Role in the Growth and Malignant Transformation of HTLV-1-Infected T Cells to Develop Adult T-Cell Leukemia. (2020)
  • Author(s): Maeda M, Tanabe-Shibuya J, Miyazato P, Masutani H, Yasunaga JI, Usami K, Shimizu A, Matsuoka M.
  • Journal Title: Frontiers in Microbiology Volume: 11 Pages: 356-356
  • DOI: 10.3389/fmicb.2020.00356
  • NAID: 120006936325
  • Peer Reviewed / Open Access
• [Journal Article] HTLV-1 bZIP factor: the key viral gene for pathogenesis. (2020)
  • Author(s): Matsuoka M, Mesnard JM.
  • Journal Title: Retroviology Volume: 17 Issue: 1 Pages: 2-2
  • DOI: 10.1186/s12977-020-0511-0
  • NAID: 120006796414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 ActivitiesIn VitroandIn Vivo (2019)
  • Author(s): Ma Guangyong、Yasunaga Jun-ichirou、Ohshima Koichi、Matsumoto Tadashi、Matsuoka Masao
  • Journal Title: Journal of Virology Volume: 93 Issue: 16
  • DOI: 10.1128/jvi.00413-19
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Latency in the Human T Cell Leukemia Virus, HTLV-1. (2019)
  • Author(s): Bangham CRM, Miura M, Kulkarni A, Matsuoka M.
  • Journal Title: Annu Rev Virol, Volume: 6 Issue: 1 Pages: 365-385
  • DOI: 10.1146/annurev-virology-092818-015501
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of Coinhibitory Receptors in Pathogenesis of Human Retroviral Infections. (2018)
  • Author(s): Yasuma-Mitobe, K., and Matsuoka, M.
  • Journal Title: Front Immunol. Volume: 9 Pages: 2755-2755
  • DOI: 10.3389/fimmu.2018.02755
  • NAID: 120006697283
  • Peer Reviewed / Open Access
• [Journal Article] afety of mogamulizumab for relapsed ATL after allogeneic hematopoietic cell. (2018)
  • Author(s): Inoue, Y., Endo, S., Matsuno, N., Kikukawa, Y., Shichijo, T., Koga, K., Takai, A., Iwanaga, K., Nishimura, N., Fuji, S., Fukuda, T., Nosaka, K., and Matsuoka, M.
  • Journal Title: Bone Marrow Transplant. Volume: 54 Issue: 2 Pages: 338-342
  • DOI: 10.1038/s41409-018-0291-5
  • Peer Reviewed / Open Access
• [Journal Article] Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2 (2018)
  • Author(s): Song Zaowen、Wu Wencai、Chen Mengyun、Cheng Wenzhao、Yu Juntao、Fang Jinyong、Xu Lingling、Yasunaga Jun-ichirou、Matsuoka Masao、Zhao Tiejun
  • Journal Title: Journal of Virology Volume: 92 Issue: 24
  • DOI: 10.1128/jvi.00909-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. (2018)
  • Author(s): Sato T, Coler-Reilly ALG, Yagishita N, Araya N, Inoue E, Furuta R, Watanabe T, Uchimaru K, Matsuoka M, Matsumoto N, Hasegawa Y, Yamano Y.
  • Journal Title: N Engl J Med. Volume: 378(6) Issue: 6 Pages: 529-538
  • DOI: 10.1056/nejmoa1704827
  • Peer Reviewed / Open Access
• [Journal Article] Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. (2018)
  • Author(s): Mahgoub M, Yasunaga JI, Iwami S, Nakaoka S, Koizumi Y, Shimura K, Matsuoka M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 6 Pages: 529-538
  • DOI: 10.1073/pnas.1715724115
  • NAID: 120006697286
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HTLV-1 Alters T Cells for Viral Persistence and Transmission (2018)
  • Author(s): Tanaka Azusa、Matsuoka Masao
  • Journal Title: Frontiers in Microbiology Volume: 9 Pages: 461-461
  • DOI: 10.3389/fmicb.2018.00461
  • NAID: 120006697284
  • Peer Reviewed / Open Access
• [Journal Article] Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo (2017)
  • Author(s): Furuta Rie、Yasunaga Jun-ichirou、Miura Michi、Sugata Kenji、Saito Akatsuki、Akari Hirofumi、Ueno Takaharu、Takenouchi Norihiro、Fujisawa Jun-ichi、Koh Ki-Ryang、Higuchi Yusuke、Mahgoub Mohamed、Shimizu Masakazu、Matsuda Fumihiko、Melamed Anat、Bangham Charles R.、Matsuoka Masao
  • Journal Title: PLOS Pathogens Volume: 13 Issue: 11 Pages: 1-22
  • DOI: 10.1371/journal.ppat.1006722
  • NAID: 120006697285
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development (2017)
  • Author(s): Yasunaga Jun-Ichirou、Matsuoka Masao
  • Journal Title: Cancer Science Volume: 109 Issue: 1 Pages: 24-32
  • DOI: 10.1111/cas.13443
  • NAID: 120006460060
  • Peer Reviewed / Open Access
• [Journal Article] HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia (2017)
  • Author(s): Takiuchi Yoko、Kobayashi Masayuki、Tada Kohei、Iwai Fumie、Sakurada Maki、Hirabayashi Shigeki、Nagata Kayoko、Shirakawa Kotaro、Shindo Keisuke、Yasunaga Jun-ichirou、Murakawa Yasuhiro、Rajapakse Vinodh、Pommier Yves、Matsuoka Masao、Takaori-Kondo Akifumi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12849-12849
  • DOI: 10.1038/s41598-017-12924-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human T-cell leukaemia virus type 1: parasitism and pathogenesis (2017)
  • Author(s): Bangham Charles R. M.、Matsuoka Masao
  • Journal Title: Philosophical Transactions of the Royal Society B: Biological Sciences Volume: 372 Issue: 1732 Pages: 20160272-20160272
  • DOI: 10.1098/rstb.2016.0272
  • NAID: 120006697287
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Critical roles of HBZ in HTLV-1 pathogenesis. (2019)
  • Author(s): Masao Matsuoka
  • Organizer: 19th International Conference on Human Retrovirology HTLV and Related Viruses
  • Int'l Joint Research / Invited
• [Presentation] Dysregulates IL-6 and IL-10-JAK/STAT Signaling and Induces Leukemia/Lymphoma CD4+T-Cell with Regulatory T-Cell-like Signatures (2019)
  • Author(s): Yusuke Higuchi, Jun-ichirou Yasunaga, Yu Mitagami, Koichi Ohshima, Masao Matsuoka.
  • Organizer: The 61st American Society of Hematology Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] ヒトT細胞白血病ウイルス１型 up-to-date (2019)
  • Author(s): 松岡 雅雄
  • Organizer: 第67回日本輸血・細胞治療学会
• [Presentation] Strategy and pathogenesis of human T-cell leukemia virus type 1. (2018)
  • Author(s): Matsuoka, M
  • Organizer: 20th Annual International Meeting of the Institute of Human Virology,
  • Int'l Joint Research / Invited
• [Presentation] ヒトT細胞白血病ウイルス１型の免疫逃避機構と治療戦略 (2018)
  • Author(s): 松岡雅雄、安永純一朗
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Presentation] HTLV-1 bZIP factorを抗原としたワクチンの開発と霊長類モデルによる効果の検証 (2017)
  • Author(s): 安永純一朗、菅田謙治、三浦未知、明里宏文、松岡雅雄
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] ヒトT細胞白血病ウイルス1型の病原性発現機構 (2017)
  • Author(s): 松岡雅雄
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] ヒトT細胞白血病ウイルス1型感染細胞の特性・体内動態に基づいた治療戦略 (2017)
  • Author(s): 松岡雅雄
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] HTLV-1がコードする2つのがん遺伝子taxとHTLV-1 bZIP factor の相反する機能と役割 (2017)
  • Author(s): 安永純一朗
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] HBZ downregulates miR-455, a tumor suppressor microRNA in ATL (2017)
  • Author(s): Ma, G., Yasunaga, JI., Miura, M., Matsumoto, T., Matsuoka, M.
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Transient expression of HTLV-1 Tax is critical event for persistence of adult T-cell leukemia cells. (2017)
  • Author(s): Mahgoub, M., Yasunaga, JI., Iwami, S., and Matsuoka,M.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] HTLV-1 bZIP factor downregulates miR-455, a tumor suppressor microRNA in ATL. (2017)
  • Author(s): Yasunaga, JI., and Matsuoka, M.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Loss of IL-6 accelerates inflammation and lymphomagenesis in HTLV-1 bZIP factor transgenic mice lymphomagenesis in HTLV-1 bZIP factor transgenic mice. (2017)
  • Author(s): Higuchi, Y., Yasunaga, J., Mitagami, Y., Ohshima, K., and Matsuoka, M.
  • Organizer: 第79回日本血液学会学術集会