Analysis of cells harboring replication-competent viruses under viral control in a macaque AIDS model

• Project/Area Number: 18H02666
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Tetsuro Matano 国立感染症研究所, エイズ研究センター, センター長 (00270653)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: ウイルス / 免疫 / HIV / 潜伏 / T細胞 / 免疫学 / 感染症 / 微生物 / 細胞傷害性T細胞 / 潜伏感染 / 細胞傷害性Tリンパ球

Outline of Final Research Achievements

Elucidation of the mechanism for persistent viral control is a key for the containment of HIV infection. It is important to control proliferation of latent but replication-competent viruses for functional HIV cure. In this study, we examined in vivo kinetics of cells harboring replication-competent viruses in HIV/SIV controllers. We found that enhancement of host immune responses targeting viral variants could be an indicator of viral blip or proliferation in HIV controllers. Furthermore, we obtained results indicating that systemic viral dissemination even in the absence of detectable viremia precedes failure in viral control. These findings provide great insights into our understanding of latent virus kinetics in HIV infection.

Academic Significance and Societal Importance of the Research Achievements

HIV感染症では、抗HIV薬治療によりエイズ発症阻止が可能となったが、治療によっても体内からウイルスを排除することができないため、感染者は生涯にわたって内服治療を継続する必要がある。さらに近年、治療によるHIV潜伏状態でも、潜伏細胞の影響で加齢関連疾患が進行することが判明したことから、潜伏細胞排除によ治癒法の開発が求められている。本研究は、HIV潜伏状態における潜伏細胞の分布・動態に関する新たな知見を見出し、その指標を明らかにしたものである。したがって、その成果は、学術的に高い意義を有するとともに、HIV潜伏状態の体内からHIV潜伏細胞を排除する治癒法構築の基盤となる点で社会的意義も大きい。

Research Products

• [Int'l Joint Research] George Washington University/University of Wisconsin-Madison/NIH(米国)
• [Int'l Joint Research] University of Miami/University of Wisconsin-Madison(米国)
• [Int'l Joint Research] University of Miami(米国)
• [Int'l Joint Research] Fred Hutchinson Cancer Research Center(米国)
• [Journal Article] Fecal Microbiome Composition in Healthy Adults in Ghana (2021)
  • Author(s): Parbie Prince Kofi、Mizutani Taketoshi、Ishizaka Aya、Kawana-Tachikawa Ai、Runtuwene Lucky Ronald、Seki Sayuri、Abana Christopher Zaab-Yen、Kushitor Dennis、Bonney Evelyn Yayra、Ofori Sampson Badu、Uematsu Satoshi、Imoto Seiya、Kimura Yasumasa、Kiyono Hiroshi、Ishikawa Koichi、Ampofo William Kwabena、Matano Tetsuro
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 74 Issue: 1 Pages: 42-47
  • DOI: 10.7883/yoken.JJID.2020.469
  • NAID: 130007973724
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2021-01-29
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Potent Anti-Simian Immunodeficiency Virus Neutralizing Antibody Induction Associated with a Germ Line Immunoglobulin Gene Polymorphism in Rhesus Macaques (2021)
  • Author(s): Matsuoka Saori、Kuwata Takeo、Ishii Hiroshi、Sekizuka Tsuyoshi、Kuroda Makoto、Sano Masato、Okazaki Midori、Yamamoto Hiroyuki、Shimizu Mikiko、Matsushita Shuzo、Seki Yohei、Saito Akatsuki、Sakawaki Hiromi、Hirsch Vanessa M.、Miura Tomoyuki、Akari Hirofumi、Matano Tetsuro
  • Journal Title: Journal of Virology Volume: 95 Issue: 7
  • DOI: 10.1128/jvi.02455-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inefficient Tax-Specific T-Cell Responses in Mice after Syngeneic Transplantation with <i>tax</i>-Transgenic Mouse-Derived Adult T-Cell Leukemia Cells (2020)
  • Author(s): Nakamura-Hoshi Midori、Suzuki Tadaki、Ainai Akira、Hasegawa Hideki、Ishii Hiroshi、Matano Tetsuro
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 73 Issue: 3 Pages: 221-225
  • DOI: 10.7883/yoken.JJID.2019.494
  • NAID: 130007845454
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2020-05-29
  • Peer Reviewed
• [Journal Article] Therapeutic vaccine-mediated Gag-specific CD8+ T-cell induction under anti-retroviral therapy augments anti-virus efficacy of CD8+ cells in simian immunodeficiency virus-infected macaques (2020)
  • Author(s): Nakamura-Hoshi Midori、Takahara Yusuke、Matsuoka Saori、Ishii Hiroshi、Seki Sayuri、Nomura Takushi、Yamamoto Hiroyuki、Sakawaki Hiromi、Miura Tomoyuki、Tokusumi Tsuyoshi、Shu Tsugumine、Matano Tetsuro
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11394-11394
  • DOI: 10.1038/s41598-020-68267-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Determination of a T cell receptor of potent CD8+ T cells against simian immunodeficiency virus infection in Burmese rhesus macaques (2020)
  • Author(s): Ishii Hiroshi、Matsuoka Saori、Ikeda Noriko、Kurihara Kyoko、Ueno Takamasa、Takiguchi Masafumi、Naruse Taeko K.、Kimura Akinori、Yokoyama Masaru、Sato Hironori、Matano Tetsuro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 4 Pages: 894-899
  • DOI: 10.1016/j.bbrc.2019.10.196
  • Peer Reviewed
• [Journal Article] A Novel Immunogen Selectively Eliciting CD8(+) T Cells but Not CD4(+) T Cells Targeting Immunodeficiency Virus Antigens. (2020)
  • Author(s): Ishii H, Terahara K, Nomura T, Takeda A, Okazaki M, Yamamoto H, Tokusumi T, Shu T, Matano T.
  • Journal Title: Journal of Virology Volume: 94 Issue: 8
  • DOI: 10.1128/jvi.01876-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD8+ T cell-based strong selective pressure on multiple simian immunodeficiency virus targets in macaques possessing a protective MHC class I haplotype (2019)
  • Author(s): Hau Trang Thi Thu、Nakamura-Hoshi Midori、Kanno Yoshiaki、Nomura Takushi、Nishizawa Masako、Seki Sayuri、Ishii Hiroshi、Kawana-Tachikawa Ai、Hall William W.、Nguyen Thi Lan Anh、Matano Tetsuro、Yamamoto Hiroyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 512 Issue: 2 Pages: 213-217
  • DOI: 10.1016/j.bbrc.2019.03.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Matrix mutations that alter Gag membrane binding modulate mature core formation and post-entry events. (2019)
  • Author(s): Hikichi, Y., E. Takeda, M. Fujino, E. Nakayama, T. Matano, and T. Murakami
  • Journal Title: Virology Volume: 532 Pages: 97-107
  • DOI: 10.1016/j.virol.2019.04.013
  • Peer Reviewed / Open Access
• [Journal Article] Human Leukocyte Antigen-Associated HIV-1 CRF02_AG <i>gag</i> and <i>vif</i> Polymorphisms in Ghana (2019)
  • Author(s): Adusei-Poku MA, Matsuoka S, Bonney EY, Abana CZ, Duker EO, Nii-Trebi NI, Ofori SB, Mizutani T, Ishizaka A, Shiino T, Kawana-Tachikawa A, Ishikawa K, Ampofo WK, Matano T
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 72 Issue: 6 Pages: 374-380
  • DOI: 10.7883/yoken.JJID.2019.201
  • NAID: 130007749423
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Estimating HIV-1 incidence in Japan from the proportion of recent infections (2019)
  • Author(s): Matsuoka Saori、Nagashima Mami、Sadamasu Kenji、Mori Haruyo、Kawahata Takuya、Zaitsu Shuichi、Nakamura Asako、de Souza Mark S.、Matano Tetsuro
  • Journal Title: Preventive Medicine Reports Volume: 16 Pages: 100994-100994
  • DOI: 10.1016/j.pmedr.2019.100994
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD8+ Cytotoxic-T-Lymphocyte Breadth Could Facilitate Early Immune Detection of Immunodeficiency Virus-Derived Epitopes with Limited Expression Levels (2019)
  • Author(s): Tsukamoto Tetsuo、Yamamoto Hiroyuki、Matano Tetsuro
  • Journal Title: mSphere Volume: 4 Issue: 1
  • DOI: 10.1128/msphere.00381-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Alternative splicing regulator RBM20 in cardiomyopathy (2018)
  • Author(s): Watanabe T, Kimura A, Kuroyanagi H
  • Journal Title: Frontiers in Molecular Biosciences Volume: 5 Issue: 2 Pages: 105-105
  • DOI: 10.1016/j.micinf.2018.10.001
  • NAID: 120007150215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The importance of accounting for testing and positivity in surveillance by time and place: an illustration from HIV surveillance in Japan (2018)
  • Author(s): Kato H.、Kanou K.、Arima Y.、Ando F.、Matsuoka S.、Yoshimura K.、Matano T.、Matsui T.、Sunagawa T.、Oishi K.
  • Journal Title: Epidemiology and Infection Volume: 146 Issue: 16 Pages: 2072-2078
  • DOI: 10.1017/s0950268818002558
  • Peer Reviewed
• [Presentation] Anti-Env antibody-independent protection of repeated intrarectal low-dose SIVmac239 challenges in rhesus macaques by vaccination inducing Gag/Vif-specific CD8+ T but not CD4+ T cells (2021)
  • Author(s): Hiroshi Ishii, Kazutaka Terahara, Takushi Nomura, Tsuyoshi Tokusumi, Tsugumine Shu, Hiromi Sakawaki, Tomoyuki Miura, Tetsuro Matano
  • Organizer: HIV R4P Virtual Conference
  • Int'l Joint Research
• [Presentation] HIV・HTLV・SARS-CoV-2に対するワクチン開発研究の現況 (2021)
  • Author(s): 俣野哲朗
  • Organizer: 日本薬学会第141回年会
  • Invited
• [Presentation] Protective efficacy of a vaccine inducing Gag/Vif-specific CD8+ T but not CD4+ T cells against repeated intrarectal low-dose SIVmac239 challenges (2020)
  • Author(s): Hiroshi Ishii, Kazutaka Terahara, Takushi Nomura, Tsuyoshi Tokusumi, Tsugumine Shu, Hiroaki Suzuki, Daisuke Fujiwara, Hiromi Sakawaki, Tomoyuki Miura, Tetsuro Matano
  • Organizer: The 23rd International AIDS Conference (AIDS 2020)
  • Int'l Joint Research
• [Presentation] GagVif特異的CD8陽性T細胞の選択的誘導によるSIV経直腸感染阻害効果 (2020)
  • Author(s): 石井洋、寺原和孝、野村拓志、徳炭剛、朱亜峰、阪脇廣美、三浦智行、俣野哲朗
  • Organizer: 第34回日本エイズ学会学術集会・総会
• [Presentation] ウイルス免疫学&免疫ウイルス学：感染免疫学の新たな理解の深化（エイズワクチン戦略から得たもの） (2020)
  • Author(s): 俣野哲朗
  • Organizer: 第34回日本エイズ学会学術集会・総会
  • Invited
• [Presentation] A novel immunogen selectively inducing Gag/Vif-specific CD8+ T but not CD4+ T cells against HIV/SIV infection (2020)
  • Author(s): Matano T
  • Organizer: AIDS Panel Meeting, U.S.-Japan Cooperative Medical Sciences Program
  • Int'l Joint Research / Invited
• [Presentation] A macaque model for analyzing the mechanism of anti-SIV neutralizing antibody induction (2019)
  • Author(s): Matano T
  • Organizer: XIV Advanced Course on HIV Pathogenesis
  • Int'l Joint Research / Invited
• [Presentation] Vaccine-induced Vif-specific CD8+ T cells exert strong suppressive pressure on acute SIV replication post-infection (2019)
  • Author(s): Ishii H, Terahara K, Nomura T, Tokusumi T, Hironaka T, Shu T, Matano T
  • Organizer: The 10th IAS Conference on HIV science (IAS2019)
  • Int'l Joint Research
• [Presentation] A vaccine selectively eliciting Gag/Vif-specific CD8+ T but not CD4+ T cells (2019)
  • Author(s): Matano T
  • Organizer: France-Japan Symposium on HIV and Hepatitis Basic Research
  • Int'l Joint Research / Invited
• [Presentation] Efficacy of vaccine-induced crossreactive CD8+ T cells targeting a Gag epitope against SIVmac239 challenge (2019)
  • Author(s): Nomura T, Terahara K, Ishii H, Yamamoto H, Miura T, Matano T
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] Contribution of vaccine-induced mutant epitope-crossreactive CD8+ T cells to stable control of SIVmac239 replication (2019)
  • Author(s): Nomura T, Terahara K, Ishii H, Yamamoto H, Miura T, Matano T
  • Organizer: The 37th annual symposium on non-human primate models for AIDS (NHP2019)
  • Int'l Joint Research
• [Presentation] ワクチン誘導Gag241-249エピトープ特異的CD8陽性T細胞の交差反応性がSIV感染に与える影響の解析 (2019)
  • Author(s): 野村拓志、寺原和孝、石井 洋、山本浩之、三浦智行、俣野哲朗
  • Organizer: 第33回日本エイズ学会学術集会
• [Presentation] Current progress in HIV vaccine development (2019)
  • Author(s): Matano T
  • Organizer: The 16th Japan-Taiwan Symposium on Communicable Diseases and Prevention, and Collaborative Project Reports
  • Int'l Joint Research / Invited
• [Presentation] HIV vaccines: Immunogen design for induction of anti-HIV immune responses (2018)
  • Author(s): Matano T
  • Organizer: 4th National HIV and AIDS Research Conference, Ghana
  • Int'l Joint Research / Invited
• [Presentation] Induction of Gag-specific CD8+ T cell responses in rhesus macaque rectum mucosa by intranasal Sendai virus vector immunization (2018)
  • Author(s): Nomura T, Ishii H, Terahara K, Yamamoto H, Miura T, Tokusumi T, Hironaka H, Shu T, Matano T
  • Organizer: The 36th annual symposium on non-human primate models for AIDS
  • Int'l Joint Research
• [Presentation] Crossreactivity of vaccine-induced CD8+ T cells targeting a Gag epitope (2018)
  • Author(s): Nomura T, Terahara K, Ishii H, Yamamoto H, Miura T, Matano T
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Gag epitope-specific CD8+ T cell responses in SIV controllers (2018)
  • Author(s): Nomura T, Ishii H, Terahara K, Yamamoto H, Matano T
  • Organizer: The 18th Kumamoto AIDS Seminar
  • Int'l Joint Research
• [Presentation] Global HIV controlに向けたワクチン開発の進展 (2018)
  • Author(s): 俣野哲朗
  • Organizer: 第22回日本ワクチン学会学術集会
  • Invited
• [Funded Workshop] XIV Advanced Course on HIV Pathogenesis (2019)