Mechanism for control of HIV-1 by cytotoxic T lymphocyte

• Project/Area Number: 17K10021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: Murakoshi Hayato 熊本大学, ヒトレトロウイルス学共同研究センター, 特任准教授 (60646123)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 細胞傷害性T細胞 / HLA / HIV-1 / CTL

Outline of Final Research Achievements

In recent T-cell AIDS vaccine trials, the vaccines did not prevent HIV-1 infection, although HIV-1-specific T cells were induced in the vaccinated individuals, suggesting that the T cells have a weak ability to suppress HIV-1 replication and fail to recognize circulating HIV-1. We previously demonstrated that the T-cell responses to 10 epitopes were significantly associated with good clinical outcome. However, there is no direct evidence that these T cells have strong abilities to suppress HIV-1 replication and recognize circulating HIV-1. Here, we demonstrated that the T cells specific for the 10 epitopes had strong abilities to suppress HIV-1 replication in vitro Moreover, the T cells cross-recognized most of the circulating HIV-1 in HIV-1-infected individuals. This study suggests the use of T cells specific for these 10 epitopes in clinical trials of T-cell vaccines as HIV-1 cure.

Academic Significance and Societal Importance of the Research Achievements

白人や黒人の感染者におけるHLA-B*27/-B*57拘束性T細胞によるHIV-1増殖抑制機構はすでに明らかとなっているが、これらのHLAは日本人を含むアジアではほとんど見られないため、日本人感染者でのT細胞によるHIV-1増殖抑制機構はまだ明らかとなっていない。したがって、日本人HIV-1感染者において、HIV-1増殖抑制に関与しているT細胞の機能解析を行うことは、日本人感染者でのT細胞によるHIV-1増殖抑制機構が明らかとなり、日本人だけでなくアジア人を対象としたHIV-1予防・治療ワクチンの開発に大いに役立つものと考えられる。

Research Products

• [Journal Article] Contribution of Proteasome-Catalyzed Peptide cis-splicing to Viral Targeting by CD8 + T Cells in HIV-1 Infection (2019)
  • Author(s): Paes W, Leonov G, Partridge T, Chikata T, Murakoshi H, Frangou A, Brackenridge S, Nicastri A, Smith AG, Learn GH , Li Y, Parker R, Oka S, Pellegrino P, Williams I, Haynes BF, McMichael AJ, Shaw GM, Hahn BH, Takiguchi M, Ternette N, Borrow P
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 116 Issue: 49 Pages: 24748-24759
  • DOI: 10.1073/pnas.1911622116
  • Peer Reviewed
• [Journal Article] Identification of immunodominant HIV-1 epitopes presented by HLA-C*12:02, a protective allele, using an immunopeptidomics approach (2019)
  • Author(s): Chikata T, Paes W, Akahoshi T, Partridge T, Murakoshi H, Gatanaga H, Ternette N, Oka S, Borrow P, Takiguchi M
  • Journal Title: Journal of Virology Volume: 93 Issue: 17
  • DOI: 10.1128/jvi.00634-19
  • Peer Reviewed
• [Journal Article] Effective suppression of HIV-1 replication by CTLs specific for Pol epitopes in conserved mosaic vaccine immunogens (2019)
  • Author(s): Zou C*, Murakoshi H*, Kuse N, Akahoshi T, Chikata T, Gatanaga H, Oka S, Hanke T, Takiguchi M (*Equal contribution)
  • Journal Title: Journal of Virology Volume: 93 Issue: 7
  • DOI: 10.1128/jvi.02142-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication (2019)
  • Author(s): Murakoshi H*, Kuse N*, Akahoshi T, Zhang Y, Chikata T, Borghan MA, Gatanaga H, Oka S, Sakai K, Takiguchi M (* equal contribution)
  • Journal Title: Journal of Virology Volume: 93 Issue: 1
  • DOI: 10.1128/jvi.01480-18
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of a single HLA-A*24:02-associated escape mutation on the detrimental effect of HLA-B*35:01 in HIV-1 control (2018)
  • Author(s): Murakoshi H, Koyanagi M, Akahoshi T, Chikata T, Kuse N, Gatanaga H, Rowland-Jones SL, Oka S, Takiguchi M
  • Journal Title: EBioMedicine Volume: 36 Pages: 103-112
  • DOI: 10.1016/j.ebiom.2018.09.022
  • Peer Reviewed / Open Access
• [Journal Article] CD8+ T cells specific for conserved, cross-reactive Gag epitopes with strong ability to suppress HIV-1 replication (2018)
  • Author(s): Murakoshi H*, Zou C*, Kuse N, Akahoshi T, Chikata T, Gatanaga H, Oka S, Hanke T, Takiguchi M (* equal contribution)
  • Journal Title: Retrovirology Volume: 15 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s12977-018-0429-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E (2017)
  • Author(s): Chikata Takayuki、Tran Giang Van、Murakoshi Hayato、Akahoshi Tomohiro、Qi Ying、Naranbhai Vivek、Kuse Nozomi、Tamura Yoshiko、Koyanagi Madoka、Sakai Sachiko、et al.
  • Journal Title: Journal of Virology Volume: 92 Issue: 5
  • DOI: 10.1128/jvi.01749-17
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype (2017)
  • Author(s): Chikata Takayuki、Murakoshi Hayato、Koyanagi Madoka、Honda Kazutaka、Gatanaga Hiroyuki、Oka Shinichi、Takiguchi Masafumi
  • Journal Title: The Journal of Infectious Diseases Volume: 216 Issue: 11 Pages: 1415-1424
  • DOI: 10.1093/infdis/jix483
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel, in-natural-infection subdominant HIV-1 CD8+ T-cell epitopes revealed in human recipients of conserved-region T-cell vaccines (2017)
  • Author(s): Nicola Borthwick, Zhansong Lin, Tomohiro Akahoshi, Anuska Llano, Sandra Silva-Arrieta, Tina Ahmed, Lucy Dorrell, Christian Brander, Hayato Murakoshi, Masafumi Takiguchi, Tomas Hanke
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: e0176418-e0176418
  • DOI: 10.1371/journal.pone.0176418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A critical role of T-cell escape mutations associated with a detrimental allele HLA-C*15:05 in poor clinical outcome of Vietnamese individuals infected with HIV-1 subtype A/E. (2020)
  • Author(s): Hayato Murakoshi, Takayuki Chikata, Tomohiro Akahoshi, Chengcheng Zou, Giang Van Tran, Trung Vu Nguyen, Kinh Van Nguyen, Nozomi Kuse, Masafumi Takiguchi
  • Organizer: 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim AIDS Panel
  • Int'l Joint Research
• [Presentation] Identification of immunodominant HIV-1 epitopes presented by HLA-C*12:02 using an immunopeptidomics approach (2019)
  • Author(s): Takayuki Chikata, Wayne Paes, Thomas Partridge, Hayato Murakoshi, Nicola Ternette, Persephone Borrow, Masafumi Takiguchi
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Different mechanisms for accumulation of Gag280 mutations between HIV-1 subtype A/E and subtype B infection (2019)
  • Author(s): Yu Zhang, Nozomi Kuse, Hayato Murakoshi, Tomohiro Akahoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] Identification of immunodominant HIV-1 epitopes presented by HLA-C*12:02 using an immunopeptidomics approach (2019)
  • Author(s): Takayuki Chikata, Wayne Paes, Thomas Partridge, Hayato Murakoshi, Nicola Ternette, Persephone Borrow, Masafumi Takiguchi
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] HIV-1 clade A/E感染者の病態に及ぼすdetrimental allele HLA-C*15:05関連T細胞逃避変異の影響 (2019)
  • Author(s): 村越 勇人, 近田 貴敬, 赤星 智寛, 滝口 雅文
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] HLA-B*35:01保有者におけるHIV-1感染促進の機序の解明 (2018)
  • Author(s): 村越 勇人, 小柳 円, 赤星 智寛, 近田 貴敬, 久世 望, 潟永 博之, 岡 慎一, 滝口 雅文
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] Selection of GagRI8 mutants by HLA-B*52:01-restricted GagRI8-specific CTLs controlling HIV-1 in HIV-1-infected Japanese individuals (2018)
  • Author(s): Yu Zhang, Nozomi Kuse, Hayato Murakoshi, Tomohiro Akahoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Generation of HIV-1 polymorphism via coevolution of multiple HIV-1-specific T cells with HIV-1 (2018)
  • Author(s): Tomohiro Akahoshi, Hiroyuki Gatanaga, Nozomi Kuse, Takayuki Chikata, Hayato Murakoshi, Naoki Ishizuka, Shinichi Oka, Masafumi Takiguchi
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Broad recognition of circulating HIV-1 by HIV-1-specific CTLs with strong ability to suppress HIV-1 replication (2018)
  • Author(s): Nozomi Kuse, Hayato Murakoshi, Tomohiro Akahoshi, Yu Zhang, Takayuki Chikata, Mohamed Ali Borghan, Hiroyuki Gatanaga, Shinichi Oka, Keiko Sakai, Masafumi Takiguchi
  • Organizer: HIVR4P 2018
  • Int'l Joint Research
• [Presentation] Control of HIV-1 by CD8+ T cells specific for epitopes of conserved mosaic vaccine immunogens (2018)
  • Author(s): Hayato Murakoshi, Chengcheng Zou, Nozomi Kuse, Tomohiro Akahoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, Tomas Hanke, Masafumi Takiguchi
  • Organizer: HIVR4P 2018
  • Int'l Joint Research
• [Presentation] Impact of a single escape mutation selected by HLA-A*24:02-restricted CD8+ T cells on HIV-1 control by HLA-B*35:01-restricted ones and T cell adaptation (2017)
  • Author(s): Hayato Murakoshi, Tomohiro Akahoshi, Madoka Koyanagi, Takayuki Chikata, Nozomi Kuse, and Masafumi Takiguchi
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 強いHIV-1増殖抑制能を有したCTLによる変異HIV-1の認識 (2017)
  • Author(s): 村越 勇人, 久世 望, 赤星 智寛, 近田 貴敬, Zhang Yu, 潟永 博之, 岡 慎一, 滝口 雅文
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] Control of HIV-1 by CTLs restricted by an HLA-B*52:01-HLA-C*12:02 protective haplotype (2017)
  • Author(s): Hayato Murakoshi, Takayuki Chikata, Madoka Koyanagi, Kazutaka Honda, Lin Zhansong, Tomohiro Akahoshi, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Impact of a single escape mutation selected by HLA-A*24:02-restricted CD8+ T cells on HIV-1 control by HLA-B*35:01-restricted ones and T cell adaptation (2017)
  • Author(s): Hayato Murakoshi, Tomohiro Akahoshi, Madoka Koyanagi, Takayuki Chikata, Katherine L James, Yoshiko Tamura, Nozomi Kuse, Xiaoming Sun, Hiroyuki Gatanaga, Sarah L Rowland-Jones, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: IAS 2017
  • Int'l Joint Research
• [Remarks] ヒトレトロウイルス学共同研究センター 国際先端研究部門 国際連携分野（滝口研究室）
  • URL: http://kumamoto-u-jrchri.jp/takiguchi/default.html
• [Remarks] ヒトレトロウイルス学共同研究センター
  • URL: http://www.caids.kumamoto-u.ac.jp/data/takiguchi/default.html
• [Remarks] 熊本大学エイズ学研究センター滝口プロジェクト研究室
  • URL: http://www.caids.kumamoto-u.ac.jp/data/takiguchi/default.html