Trial of CD4 positive T cell induction from iPS cells

• Project/Area Number: 16H05194
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Osaka University
• Principal Investigator: Shioda Tatsuo 大阪大学, 微生物病研究所, 教授 (00187329)
• Co-Investigator(Kenkyū-buntansha): 明里 宏文 京都大学, 霊長類研究所, 教授 (20294671) ; 金子 新 京都大学, iPS細胞研究所, 准教授 (40361331)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: iPS / CD4 / TRIM5 / CCR5 / サル / iPS細胞 / アカゲザル / 移植・再生医療

Outline of Final Research Achievements

To develop a method to induce CD4 positive T cells from iPS cells, we established several iPS cell clones from rhesus monkeys. We tried several methods to introduce CRISPR/Cas9 into iPS cells and succeeded in destroying anti-HIV-1 TRIM5 gene. We are now preparing large amount of iPS cells in which HIV-1 co-receptor gene was swapped with truncated EGFR-marker gene for injection into animals. The transfusion of iPS cell-derived hematopoietic stem cells into animal will facilitate differentiation of iPS cells to CD4 positive cells in vivo.

Academic Significance and Societal Importance of the Research Achievements

HIV感染症の治癒を目指して、HIVに感染しないCD4陽性T細胞をiPS細胞から誘導することを目的とした。これまで、iPS細胞からCD4陽性T細胞を試験管内で分化誘導した成功例の報告はない。よって、CD4陽性T細胞ではなく、未分化な造血幹細胞を個体に移入することによりCD4陽性T細胞への誘導を計画したが、実験動物として使用可能なアカゲザルのiPS細胞はヒトのiPS細胞とは様々な面で異なることが明らかとなり、現在までにはサルへの移入実験には残念ながら至らなかった。しかし、アカゲザルiPS細胞特有の性質への理解は深まり、今度の研究の進展に役立つ知見は得られた

Research Products

• [Journal Article] Relationship between genome packaging and Gag translation/AUG of primate lentiviruses (2019)
  • Author(s): Sakuragi Sayuri、Shioda Tatsuo、Sakuragi Jun-ichi
  • Journal Title: Microbes and Infection Volume: 21 Issue: 2 Pages: 119-123
  • DOI: 10.1016/j.micinf.2018.09.002
  • Peer Reviewed / Open Access
• [Journal Article] PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation (2019)
  • Author(s): Miyakawa K, Matsunaga S, Yokoyama M, Nomaguchi M, Kimura Y, Nishi M, Kimura H, Sato H, Hirano H, Tamura T, Akari H, Miura T, Adachi A, Sawasaki T, Yamamoto N, Ryo A
  • Journal Title: Nature Communications Volume: 印刷中
  • NAID: 120006949469
  • Peer Reviewed
• [Journal Article] Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility (2019)
  • Author(s): Xu Huaigeng、Wang Bo、Ono Miyuki、Kagita Akihiro、Fujii Kaho、Sasakawa Noriko、Ueda Tatsuki、Gee Peter、Nishikawa Misato、Nomura Masaki、Kitaoka Fumiyo、Takahashi Tomoko、Okita Keisuke、Yoshida Yoshinori、Kaneko Shin、Hotta Akitsu
  • Journal Title: Cell Stem Cell Volume: 24 Issue: 4 Pages: 566-578.e7
  • DOI: 10.1016/j.stem.2019.02.005
  • Peer Reviewed / Open Access
• [Journal Article] Developing thymus-on-a-chip and cancer-on-a-chip for cancer immunotherapy. (2019)
  • Author(s): Torisawa Y, Mishima Y, Kaneko S
  • Journal Title: Impact Volume: 29 Pages: 33-35
  • Peer Reviewed
• [Journal Article] Toward the development of true “off-the-shelf” synthetic T-cell immunotherapy (2019)
  • Author(s): Iriguchi Shoichi、Kaneko Shin
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 16-22
  • DOI: 10.1111/cas.13892
  • NAID: 120006547385
  • Peer Reviewed / Open Access
• [Journal Article] Diversity of <i>ULBP5</i> in Old-World monkeys (Cercopithecidae) and divergence of the <i>ULBP</i> gene family in primates (2018)
  • Author(s): NARUSE Taeko K.、AKARI Hirofumi、MATANO Tetsuro、KIMURA Akinori
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 94 Issue: 10 Pages: 441-453
  • DOI: 10.2183/pjab.94.029
  • NAID: 130007529110
  • ISSN: 0386-2208, 1349-2896
  • Year and Date: 2018-12-11
  • Peer Reviewed
• [Journal Article] Defects in assembly explain reduced antiviral activity of the G249D polymorphism in human TRIM5α. (2018)
  • Author(s): KomurluS, Bradley M, Smolin N, Imam S, Pauszek RF 3rd, Robia SL, Millar D, Nakayama EE, Shioda T, Campbell EM.
  • Journal Title: PLOS ONE Volume: 14 Issue: 3 Pages: 1-20
  • DOI: 10.1371/journal.pone.0212888
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] External Quality Assessment Scheme for HIV-1 Drug-Resistance Genotyping in Thailand (2018)
  • Author(s): Saeng-aroon Siriphan、Saipradit Nonglak、Loket Ruangchai、Klamkhai Nattapong、Boonmuang Ratrawee、Kaewprommal Pavita、Prommajan Korrakot、Takeda Naokazu、Sungkanuparph Somnuek、Shioda Tatsuo、Sangkitporn Somchai、Motomura Kazushi
  • Journal Title: AIDS Research and Human Retroviruses Volume: 34 Issue: 12 Pages: 1028-1035
  • DOI: 10.1089/aid.2017.0299
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Naturally Occurring Mutations in HIV-1 CRF01_AE Capsid Affect Viral Sensitivity to Restriction Factors (2018)
  • Author(s): Nakayama Emi E.、Saito Akatsuki、Sultana Tahmina、Jin Zhuan、Nohata Kyotaro、Shibata Masato、Hosoi Miho、Motomura Kazushi、Shioda Tatsuo、Sangkitporn Somchai、Loket Ruangchai、Saeng-aroon Siriphan
  • Journal Title: AIDS Research and Human Retroviruses Volume: 34 Issue: 4 Pages: 382-392
  • DOI: 10.1089/aid.2017.0212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Understanding the facts and minding the gap of (HIV-1/HIV-2) primate research and infectious disease laboratories in Africa. (2018)
  • Author(s): Ejikeugwu C, Eze P, Iroha I, Esimone C, Adikwu M, Akari H,
  • Journal Title: International Journal of Virology and AIDS Volume: 5 Pages: 046-046
  • Peer Reviewed
• [Journal Article] Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA. (2018)
  • Author(s): Higaki K, Hirao M, Kawana-Tachikawa A, Iriguchi S, Kumagai A, Ueda N, Bo W, Kamibayashi S, Watanabe A, Nakauchi H, Suzuki K, Kaneko S.
  • Journal Title: Mol Ther Nucleic Acids Volume: 12 Pages: 723-804
  • DOI: 10.1016/j.omtn.2018.07.017
  • NAID: 120006649570
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response. (2018)
  • Author(s): Ueda N, Uemura Y, Zhang R, Kitayama S, Iriguchi S, Kawai Y, Yasui Y, Tatsumi M, Ueda T, Liu TY, Mizoro Y, Okada C, Watanabe A, Nakanishi M, Senju S, Nishimura Y, Kuzushima K, Kiyoi H, Naoe T, Kaneko S
  • Journal Title: Stem Cell Reports Volume: 10 Issue: 6 Pages: 1935-1946
  • DOI: 10.1016/j.stemcr.2018.04.025
  • NAID: 120006473765
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repurposing the Cord Blood Bank for Haplobanking of HLA-Homozygous iPSCs and Their Usefulness to Multiple Populations (2018)
  • Author(s): Lee Suji、Huh Ji Young、Turner David M.、Lee Soohyeon、Robinson James、Stein Jeremy E.、Shim Sung Han、Hong Chang Pyo、Kang Myung Seo、Nakagawa Masato、Kaneko Shin、Nakanishi Mahito、Rao Mahendra S.、Kurtz Andreas、Stacey Glyn N.、Marsh Steven G.E.、Turner Marc L.、Song Jihwan
  • Journal Title: STEM CELLS Volume: 36 Issue: 10 Pages: 1552-1566
  • DOI: 10.1002/stem.2865
  • Peer Reviewed / Open Access
• [Journal Article] Enhancing T cell Receptor Stability in Rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy (2018)
  • Author(s): Minagawa A, Yoshikawa T, Yasukawa M, Hotta A, Kunitomo M, Iriguchi S, Takiguchi M, Kassai Y, Imai E, Yasui Y, Kawai Y, Zhang R, Uemura Y, Miyoshi H, Nakanishi M, Watanabe A, Hayashi A, Kawana K, Fujii T, Nakatsura T, Kaneko S
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 6 Pages: 850-858
  • DOI: 10.1016/j.stem.2018.10.005
  • Peer Reviewed / Open Access
• [Journal Article] Immune cell therapy using iPS cells (2018)
  • Author(s): 矢野 寿、金子 新
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 2 Pages: 225-231
  • DOI: 10.11406/rinketsu.59.225
  • NAID: 130006441933
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors (2018)
  • Author(s): Oshima Koichi、Watanabe Akira、Nakahata Tatsutoshi、Saito Megumu K. et al.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 497 Issue: 2 Pages: 719-725
  • DOI: 10.1016/j.bbrc.2018.02.139
  • NAID: 120006466601
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of H5N1 influenza virus quasispecies with adaptive hemagglutinin mutations from single-virus infections of human airway cells (2018)
  • Author(s): 1.Watanabe Y**, Arai Y, Kawashita N, Ibrahim MS, Elgendy EM, Daidoji T, Kajikawa J, Hiramatsu H, Sriwilaijaroen N, Ono T, Takagi T, Takahashi K, Shioda T, Matsumoto K, Suzuki Y, Nakaya T
  • Journal Title: J Virol. Volume: 印刷中 Issue: 11
  • DOI: 10.1128/jvi.02004-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Variation at position 350 in the Chikungunya virus 6K-E1 protein determines the sensitivity of detection in a rapid E1-antigen test (2018)
  • Author(s): Tuekprakhon Aekkachai、Nakayama Emi E.、Bartholomeeusen Koen、Puiprom Orapim、Sasaki Tadahiro、Huits Ralph、Luplertlop Natthanej、Kosoltanapiwat Nathamon、Maneekan Pannamas、Ari?n Kevin K.、Shioda Tatsuo、Leaungwutiwong Pornsawan
  • Journal Title: Sci Rep Volume: 8 Issue: 1
  • DOI: 10.1038/s41598-018-19174-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mapping Region of Human Restriction Factor APOBEC3H Critical for Interaction with HIV-1 Vif (2017)
  • Author(s): Nakashima Masaaki、Tsuzuki Shinya、Awazu Hiroaki、Hamano Akiko、Okada Ayaka、Ode Hirotaka、Maejima Masami、Hachiya Atsuko、Yokomaku Yoshiyuki、Watanabe Nobuhisa、Akari Hirofumi、Iwatani Yasumasa
  • Journal Title: Journal of Molecular Biology Volume: 429 Issue: 8 Pages: 1262-1276
  • DOI: 10.1016/j.jmb.2017.03.019
  • Peer Reviewed
• [Journal Article] Critical Contribution of Tyr15 in the HIV-1 Integrase (IN) in Facilitating IN Assembly and Nonenzymatic Function through the IN Precursor Form with Reverse Transcriptase. (2017)
  • Author(s): Takahata T, Takeda E, Tobiume M, Tokunaga K, Yokoyama M, Huang YL, Hasegawa A, Shioda T, Sato H, Kannagi M, Masuda T.
  • Journal Title: J Virol Volume: 91 Issue: 1
  • DOI: 10.1128/jvi.02003-16
  • Peer Reviewed / Open Access
• [Journal Article] BCR-ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells (2016)
  • Author(s): Ueda N, Zhang R, Tatsumi M, Liu TY, Kitayama S, Yasui Y, Sugai S, Iwama T, Senju S, Okada S, Nakatsura T, Kuzushima K, Kiyoi H, Naoe T, Kaneko S, Uemura Y.
  • Journal Title: Cell Mol Immunol. Volume: - Issue: 1 Pages: 15-26
  • DOI: 10.1038/cmi.2016.7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model (2016)
  • Author(s): Yokokawa H., Higashino A., Suzuki S., Moriyama M., Nakamura N., Suzuki T., Suzuki R., Ishii K., Kobiyama K., Ishii KJ., Wakita T., Akari H. and Kato T.
  • Journal Title: Gut Volume: in press Issue: 2 Pages: 372-379
  • DOI: 10.1136/gutjnl-2016-312208
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SL1 revisited: functional analysis of the structure and conformation of HIV-1 genome RNA. (2016)
  • Author(s): Sakuragi S, Yokoyama M, Shioda T, Sato H, Sakuragi JI.
  • Journal Title: Retrovirology Volume: 13 Issue: 1 Pages: 79-79
  • DOI: 10.1186/s12977-016-0310-9
  • Peer Reviewed / Open Access
• [Journal Article] HIV-1 Vpr Abrogates the Effect of TSG101 Overexpression to Support Virus Release. (2016)
  • Author(s): Chutiwitoonchai N, Siarot L, Takeda E, Shioda T, Ueda M, Aida Y.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0163100-e0163100
  • DOI: 10.1371/journal.pone.0163100
  • Peer Reviewed / Open Access
• [Journal Article] Circulation of HIV-1 Multiple Complexity Recombinant Forms Among Female Sex Workers Recently Infected with HIV-1 in Thailand. (2016)
  • Author(s): Saeng-Aroon S, Loket R, Plipat T, Lumyai S, Chu PY, Sangkitporn S, Nakayama EE, Takeda N, Shioda T, Motomura K.
  • Journal Title: AIDS Res Hum Retroviruses Volume: 32 Issue: 7 Pages: 694-701
  • DOI: 10.1089/aid.2015.0371
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by randam mutagenesis. (2016)
  • Author(s): Sultana, T., Nakayama, E.E., Tobita, S., Yokoyama, M., Seki, Y., Saito, A., Nomaguchi, M., Adachi, A., Akari, H., Sato, H., and Shioda, T.
  • Journal Title: Journal of General Virology Volume: 97 Issue: 4 Pages: 963-976
  • DOI: 10.1099/jgv.0.000408
  • Peer Reviewed / Open Access
• [Presentation] 再生医療等製品の若手開発者による薬事承認に向けた開発と課題 (2019)
  • Author(s): 金子新
  • Organizer: 第18回日本再生医療学会 シンポジウム39
  • Invited
• [Presentation] Multiple pathways to avoid IFN-β sensitivity of HIV-1 by mutants capsid (2018)
  • Author(s): Akatsuki Saito,Joa0 I Mamede,Tahmina Sultana,Hirotaka Ode,Kyoutaro Nohata,Emi Nakayama,Yasumasa Iwatani,Thomas J Hope,Tatsuo Shioda
  • Organizer: Retroviruses 2018
  • Int'l Joint Research
• [Presentation] Naturally Occurring Mutations in HIV-1 CRF01_AE Capsid Affect Viral Sensitivity to Restriction Factors (2018)
  • Author(s): Nakayama EE, Saito A, Sultana T, Jin Z, Nohata K, Shibata M, Hosoi M, Motomura K, Shioda T, Sangkitporn S, Loket R, Saeng-Aroon S.
  • Organizer: The 17th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research
• [Presentation] The Q4R mutation accelerates Kinetics of reverse transcription and initiation of uncoating of IFN-β hypersensitive HIV-1 capsid mutant (2018)
  • Author(s): Akatsuki Saito, Joao I Mamede, Tahmina Sultana, kyoutaro Nohata, Emi E nakayama, Tatsuo Shioda, Thomas J Hope.
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] HIV-1カプシドによるI型インターフェロン感受性の制御 (2018)
  • Author(s): 齊藤 暁
  • Organizer: 第32回日本エイズ学会学術集会
• [Presentation] カプシド182番目アミノ酸残基のCPSF6結合への寄与はHIV-1とHIV-2で異なる (2018)
  • Author(s): 齊藤 暁, 大出裕高,野畑享太郎,大森久樹,中山英美,岩谷靖雅,塩田達雄
  • Organizer: 第32回日本エイズ学会学術集会
• [Presentation] A novel PKC actvator 10-Methyl-Aplog-1 in combination with JQ1 showed high potency as LRA for shock and kill therapy (2018)
  • Author(s): Ayaka Washizaki, Megumi Murata, Yohei Seki, Yin Pui Tang, Hiroyuki Kangawa, Tan Wei Keat, Kazuhiro Irie, Hirofumi Akari
  • Organizer: 36th Annual Symposium Nonhuman Primate Models for AIDS
  • Int'l Joint Research
• [Presentation] Cooperative cellular and humoral immunity may contribute to the efficient control of HIV-1 replication in macaques. (2018)
  • Author(s): Yohei Seki, Akatsuki Saito, Shigeyoshi Harada, Ayaka Washizaki, Megumi Murata, Yuta Hikichi, Kazuhisa Yoshimura, Hiroshi Ishii, Yorifumi Satou, Islam Mohammad Saiful, Hirotaka Ode, Yasumasa Iwatani, Takeshi Yoshida, Yasuhiro Yasutomi, Tetsuro Matano, Tomoyuki Miura, Hirofumi Akari
  • Organizer: 36th Annual Symposium Nonhuman Primate Models for AIDS
  • Int'l Joint Research
• [Presentation] Molecular characterization of the env gene during transmission of macaque-tropic human immunodeficiency virus type 1 (HIV-1mt) (2018)
  • Author(s): Shigeyoshi Harada, Yuta Hikichi, Yohei Seki, Yasumasa Iwatani, Yasuhiro Yasutomi, Tomoyuki Miura, Tetsuro Matano, Hirofumi Akari, Kazuhisa Yoshimura
  • Organizer: 36th Annual Symposium Nonhuman Primate Models for AIDS
  • Int'l Joint Research
• [Presentation] A novel PKC activator 10-Methyl-Aplog-1 in combination with JQ1 showed high potency as LRA for shock and kill therapy. (2018)
  • Author(s): Ayaka Washizaki, Megumi Murata, Yohei Seki, Yin Pui Tang, Hiroyuki Kangawa, Kazuhiro Irie, Hirofumi Akari
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 新しいHIV感染霊長類モデル：HIV感染症の根治に向けて (2018)
  • Author(s): 明里宏文
  • Organizer: 第14回霊長類医科学フォーラム
  • Invited
• [Presentation] 新規PKC活性化剤10-Methyl-Aplog-1とJQ1の併用はLatency Reversing Agentとして理想的な活性を示す (2018)
  • Author(s): 鷲崎彩夏, 村田めぐみ, 関洋平, Yin Pui Tang, 寒川裕之, Wei Keat Tan, 入江一浩, 明里宏文
  • Organizer: 第32回 日本エイズ学会学術集会・総会
• [Presentation] HIV感染霊長類モデルによるHIV根治研究 (2018)
  • Author(s): 明里宏文
  • Organizer: 第32回 日本エイズ学会学術集会・総会
  • Invited
• [Presentation] T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for cancer immunotherapy. (2018)
  • Author(s): Minagawa A, Hotta A, Kawai Y, Yasui Y, Uemura Y, Yasukawa Y, Nakatsura T, Kaneko S.
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] iPS細胞からのヒト免疫細胞再生 (2018)
  • Author(s): 金子新
  • Organizer: 第29回日本生体防御学学会学術総会
  • Invited
• [Presentation] HLA homologous iPS cell project for regenerative medicine. (2018)
  • Author(s): Kaneko S
  • Organizer: Frontier iPS and Stem Cell Therapeutic Summit 2018 in Taipei
  • Int'l Joint Research / Invited
• [Presentation] Enhancing T cell receptor stability confirm antigen specificity of regenerated T cell (2018)
  • Author(s): 金子新
  • Organizer: 第18回日本再生医療学会ISCT Joint Symposium
  • Invited
• [Presentation] カプシド領域の変異はHIV-1のIFV感受性を制御する (2017)
  • Author(s): Akatsuki Saito, Tahmina Sultana, Hirotaka Obe, Yasumasa Iwatani, Emi Nakayama, Tatsuo Shioda
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] Mutations in viral capsid modulate IFN-β sensitivity of HIV-1. (2017)
  • Author(s): Sultana T, Saito A, Ode H, Iwatani Y, Nakayama E, Shioda T.
  • Organizer: 第65回日本ウイルス学会
• [Presentation] Natural Mutations In Capsid Of HIV-1 CRF01AE Aaffect the Sensitivity to Restriction Factors. (2017)
  • Author(s): Emi E..Nakayama, Tahmina Sultana, Zhuan.Jin, Kyoutaro.Nohata, Masato.Shibata, Miho.Hosoi, Kazushi Motomura, Tatsuo Shioda, Somcchai Sangkitporm, Ruangchai Loket, Siriphan Seang-aroon.
  • Organizer: Retroviruses 2017
  • Int'l Joint Research