Development of immunotherapy for HIV cure

• Project/Area Number: 25293226
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: National Institute of Infectious Diseases (2014-2015); The University of Tokyo (2013)
• Principal Investigator: Tachikawa Ai 国立感染症研究所, エイズ研究センター, 室長 (10396880)
• Co-Investigator(Kenkyū-buntansha): KANEKO Shin 京都大学, iPS細胞研究所, 教授 (40361331) ; KOIBUCHI Tomohiko 東京大学, 医科学研究所, 講師 (50313094)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2015: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: HIV感染症 / CTL / iPS細胞 / 免疫細胞療法 / 免疫老化 / 抗原特異的CTL

Outline of Final Research Achievements

Toward achievement of the HIV eradication strategy, we developed a new T cell therapy using induced pluripotent stem (iPS) cell technology. T cells are irreversibly senescent, less survival, dysfunctional, and lose potential for HIV suppression in chronic HIV-1 infection. We successfully generated iPS cells from HIV-specific cytotoxic T lymphocytes (CTLs) in HIV-infected patients (T-iPSC), and redifferentiated the T-iPSC into T cells with the same antigen specificity. The T-iPSC-derived T cells had high proliferation capacity and produced multiple cytokines. HIV-infected cells were recognized and killed by the T-iPSC-derived HIV-specific T cells efficiently, suggesting rejuvenated T-iPSC-derived T cells could be a good effector in vivo. Our data show the possibility that immunotherapy using T-iPSC-derived HIV-specific T cells could be a new strategy for eradicating HIV-infected cells to achieve HIV cure.

Research Products

• [Int'l Joint Research] Simon Fraser University(カナダ)
• [Journal Article] Short intracellular HIV-1 transcripts as biomarkers of residual immune activation in patients on antiretroviral therapy. (2016)
  • Author(s): Ishizaka A, Sato H, Nakamura H, Kota M, Kikuchi T, Hosoya N, Koibuchi T, Kawana-Tachikawa A, Mizutani T.
  • Journal Title: Journal of Virology Volume: 90
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Rapid HIV-1 disease progression in individuals infected with a virus adapted to its host population. (2016)
  • Author(s): Katoh J, Kawana-Tachikawa A, Shimizu A, Zhu D, Han C, Nakamura H, Koga M, Kikuchi T, Adachi E, Koibuchi T, Gao GF, Brumme ZL, Iwamoto A.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0150397-e0150397
  • DOI: 10.1371/journal.pone.0150397
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy. (2015)
  • Author(s): Ando M, Nishimura T, Yamazaki S, Yamaguchi T, Kawana-Tachikawa A, Hayama T, Nakauchi Y, Ando J, Ota Y, Takahashi S, Nishimura K, Ohtaka M, Nakanishi M, Miles JJ, Burrows SR, Brenner MK, Nakauchi H.
  • Journal Title: Stem Cell Reports. Volume: 5(4) Issue: 4 Pages: 597-608
  • DOI: 10.1016/j.stemcr.2015.07.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection. (2015)
  • Author(s): Merlbe SC, Hasan Z, Mahiti M, Toyoda M, Mori M, Gatanaga H, Kikuchi T, Miura T, Kawana-Tachikawa A, Iwamoto A, Oka S, Ueno T.
  • Journal Title: Archives of Virology Volume: 160 Pages: 2033-2041
  • Peer Reviewed
• [Journal Article] Anti-APOBEC3G Activity of HIV-1 Vif Protein Is Attenuated in Elite Controllers. (2015)
  • Author(s): Kikuchi T, Iwabu Y, Tada T, Kawana-Tachikawa A, Koga M, Hosoya N, Nomura S, Brumme ZL, Jessen H, Pereyra F, Trocha A, Walker BD, Iwamoto A, Tokunaga K, Miura T.
  • Journal Title: Journal of Virology Volume: 89 Issue: 9 Pages: 4992-5001
  • DOI: 10.1128/jvi.03464-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Epigenetic repression of interleukin-2 expression in senescent CD4+ T cells during chronic human immunodeficiency virus type-1 infection. (2015)
  • Author(s): Nakayama-Hosoya K, Ishida T, Youngblood B, Nakamura H, Hosoya N, Koga M, Koibuchi T, Iwamoto A, Kawana-Tachikawa A.
  • Journal Title: Journal of Infectious Diseases Volume: 2112 Issue: 1 Pages: 28-39
  • DOI: 10.1093/infdis/jiu376
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development and Customization of a Color-Coded Microbeads-Based Assay for Drug Resistance in HIV-1 Reverse Transcriptase. (2014)
  • Author(s): Gu L, Kawana-Tachikawa A, Shiino T, Nakamura H, Koga M, Kikuchi T, Adachi E, Koibuchi T, Ishida T, Gao GF, Matsushita M, Sugiura W, Iwamoto A, Hosoya N.
  • Journal Title: PLoS One Volume: 9 Issue: 10 Pages: e109823-e109823
  • DOI: 10.1371/journal.pone.0109823
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Switching and emergence of CTL epitopes in HIV-1 infection (2014)
  • Author(s): Han, C., Kawana-Tachikawa, A., Shimizu, A., Zhu D., Nakamura, H., Adachi, E., Kikuchi, T., Koga, M., Koibuchi, T., Gao, G.F., Sato, Y., Yamagata, A., Martin, E., Fukai, S., Brumme, Z.L.,Iwamoto, A.
  • Journal Title: Retrovirolgy Volume: 11 Issue: 1 Pages: 38-38
  • DOI: 10.1186/1742-4690-11-38
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals. (2014)
  • Author(s): Kawana-Tachikawa A, Llibre JM, Bravo I, Escrig R, Mothe B, Puig J, Puertas MC, Martinez-Picado J, Blanco J, Manzardo C, Miro JM, Iwamoto A, Pozniak AL, Gatell JM, Clotet B, Brander C; MARAVIBOOST investigators.
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: e87334-e87334
  • DOI: 10.1371/journal.pone.0087334
  • Peer Reviewed
• [Journal Article] Structure of TCR and antigen complexes at an immunodominant CTL epitope in HIV-1 infection (2013)
  • Author(s): Shimizu, A., Kawana-Tachikawa. A., Yamagata, A., Han, C., Zhu, D., Sato, Y., Nakamura, H., Koibuchi, T., Carlson, J., Martin, E., Brumme, C.J., Shi, Y., Gao, G.F., Brumme, Z.L., Fukai, S., Iwamoto, A.
  • Journal Title: Scientific Reports Volume: 3 Issue: 1 Pages: 3097-3097
  • DOI: 10.1038/srep03097
  • Peer Reviewed
• [Journal Article] Development of a rapid cell-fusion-based phenotypic HIV-1 tropism assay. (2013)
  • Author(s): Teeranaipong P, Hosoya N, Kawana-Tachikawa A, Fujii T, Koibuchi T, Nakamura H, Koga M, Kondo N, Gao GF, Hoshino H, Matsuda Z, Iwamoto A.
  • Journal Title: Journal of the International AIDS Society. Volume: 16 Issue: 1 Pages: 18723-18732
  • DOI: 10.7448/ias.16.1.18723
  • Peer Reviewed
• [Presentation] 多ウイルス特異的T細胞療法における標的部位の同定法の確立 (2015)
  • Author(s): 立川（川名）愛、小野敏明、藤田由利子、田中ゆきえ、高橋聡、森尾友宏
  • Organizer: 第７回血液疾患免疫療法研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-26
• [Presentation] HIV-1感染におけるCD4陽性T細胞のIL2遺伝子発現低下分子メカニズムの解明． (2014)
  • Author(s): 細谷(中山)香、石田尚臣、中村仁美、細谷紀彰、古賀道子、鯉渕智彦、岩本愛吉、立川(川名)愛
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] HIV感染者のCD8陽性T細胞における補助刺激分子OX40の検討 (2014)
  • Author(s): 佐藤秀憲、細谷(中山)香、菊地正、安達英輔、古賀道子、中村仁美、鯉渕智彦、岩本愛吉、立川(川名)愛
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] 恒常的に培養維持されたCD4陽性T細胞へのHIV-1の感染とその転写制御機構の解明 (2014)
  • Author(s): 和田倭、小林(石原)美栄、寺原和孝、池野翔太、徳永研三、立川(川名)愛、山岸誠、竹山春子、横田(恒次)恭子
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Proposal of new immune cell source for HIV-1 infection study based on iPSCs and evaluation of impact of viral replication in iPSCs-derived macrophage expressing shRNAs targeting HIV-1 promoter. (2014)
  • Author(s): Hirao M, Suzuki K, Kawana-Tachikawa A, Nakauchi H, Cooper DA, Kelleher AD, Kaneko S.
  • Organizer: The 20th International AIDS Conference
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2014-07-20 – 2014-07-25
• [Presentation] Disruption of T cell immunity during chronic HIV-1 infection. (2014)
  • Author(s): Ai Kawana-Tachikawa
  • Organizer: The 21st East Asia Joint Symposium on Biomedical Research
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-07-17 – 2014-07-18
  • Invited
• [Presentation] Low IL-2 expression by epigenetic modification is associated with immunosenescence in HIV non-controllers. (2014)
  • Author(s): Kaori Nakayama-Hosoya, Takaomi Ishida, Noriaki Hosoya, Hitomi Nakamura, Michiko Koga, Tomohiko Koibuchi, Aikichi Iwamoto, Ai Kawana-Tachikawa.
  • Organizer: Keystone symposia, HIV Pathogenesis – Virus vs Host.
  • Place of Presentation: Banff, Alberta, Canada
• [Presentation] The essential role of epigenetic regulation for CD4+ T cell dysfunction during chronic HIV-1 infection. (2013)
  • Author(s): Kaori Nakayama-Hosoya, Takaomi Ishida, Noriaki Hosoya, Hitomi Nakamura, Michiko Koga, Tomohiko Koibuchi, Aikichi Iwamoto, Ai Kawana-Tachikawa.
  • Organizer: AIDS Vaccine 2013 Conference
  • Place of Presentation: Barcelona, Spain
• [Presentation] 重複するCTLエピトープ部位に生じた１アミノ酸変異によるエピトープの消滅と出現 (2013)
  • Author(s): 立川（川名）愛、韓忠勇、清水晃尚、細谷紀彰、中村仁美、古賀道子、鯉渕智彦、岩本愛吉
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Interaction between virus and host immune response during chronic HIV-1 infection.
  • Author(s): Ai Kawana-Tachikawa
  • Organizer: The 9th China-Japan Laboratory Workshop: Pathogenesis, Gene regulation, and signal transduction.
  • Place of Presentation: Beijing, China
  • Invited
• [Presentation] HIV感染症に対する免疫細胞療法の可能性
  • Author(s): 立川（川名）愛
  • Organizer: 第５回造血器腫瘍免疫療法研究会
  • Place of Presentation: 名古屋
  • Invited