Study on HIV-1-specific cytotoxic T lymphocytes responsible for AIDS progression in HIV-1-infected individuals

• Project/Area Number: 15K19588
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: MURAKOSHI HAYATO 熊本大学, エイズ学研究センター, 特任講師 (60646123)
• Research Collaborator: GATANAGA Hiroyuki ; CHIKATA Takayuki ; AKAHOSHI Tomohiro
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 細胞傷害性T細胞 / HIV / HLA

Outline of Final Research Achievements

To clarify this mechanism, we identified HLA-B*35:01-restricted epitope-specific CD8+ T cells controlling HIV-1 in 63 HIV-1 clade B-infected Japanese individuals having HLA-B*35:01 and further analyzed the effect of mutations within the epitopes on the T cell responses. The T cell responses to GagNY9, PolVY10, NefRY11, or YF9 epitopes were significantly associated with low plasma viral load. A breadth of the T cell responses to these 4 epitopes was inversely correlated with it. The control of HIV-1 by YF9-specific T cells are impaired by NefY135F mutation associated with HLA-A*24:02. The ex vivo longitudinal analysis of the YF9-specific T cells showed that the Y135F mutant-specific T cells and wild type-specific/cross-reactive T cells were elicited before and after an emergence of the mutant virus. However, the former T cells failed to control HIV-1 replication whereas the latter T cells contributed to the control of HIV-1.

Research Products

• [Journal Article] Accumulation of Pol Mutations Selected by HLA-B*52:01-C*12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses. (2017)
  • Author(s): Murakoshi H, Koyanagi M, Chikata T, Rahman MA, Kuse N, Sakai K, Gatanaga H, Oka S, Takiguchi M.
  • Journal Title: J Virol. Volume: 91(4) Issue: 4
  • DOI: 10.1128/jvi.02082-16
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel conserved-region T-cell mosaic vaccine with high global HIV-1 coverage is recognized by protective responses in untreated infection (2016)
  • Author(s): Beatrice Ondondo, Hayato Murakoshi, Genevieve Clutton, Sultan Abdul-Jawad, Edmund G.-T. Wee, Hiroyuki Gatanaga, Shinichi Oka, Andrew J. McMichael, Masafumi Takiguchi, Bette Korber and Tomas Hanke
  • Journal Title: Molecular Therapy Volume: 24 Issue: 4 Pages: 832-842
  • DOI: 10.1038/mt.2016.3
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A strong association of HLA-associated Pol and Gag mutations with clinical parameters (2016)
  • Author(s): Giang Van Tran,* Takayuki Chikata,* Jonathan M. Carson, Hayato Murakoshi, Dung Hoai Nguyen, Yoshiko Tamura, Tomohiro Akahoshi, Nozomi Kuse, Keiko Sakai, Sachiko Sakai, Kyle Cobarrubias, Shinichi Oka, Zabrina L. Brumme, Kinh Van Nguyen, and Masafumi Takiguchi, (*Equal contribution)
  • Journal Title: AIDS Volume: 30 Issue: 5 Pages: 681-689
  • DOI: 10.1097/qad.0000000000000969
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations (2015)
  • Author(s): Nozomi Kuse*, Mohammad Arif Rahman*, Hayato Murakoshi*, Giang Van Tran, Takayuki Chikata, Madoka Koyanagi, Kinh Van Nguyen, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi, (*Equal contribution)
  • Journal Title: Journal of Virology Volume: 89 Issue: 14 Pages: 7363-7372
  • DOI: 10.1128/jvi.00974-15
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Impact of a Single HLA-A*24:02-associated Escape Mutation on HLA-B*35:01-associated HIV-1 Control and T cell Adaptation (2016)
  • 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: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: 鹿児島県鹿児島市（かごしま県民交流センター）
  • Year and Date: 2016-11-24
  • Invited
• [Presentation] ベトナム人HIV-1サブタイプA/E感染者コホートにおけるエイズ病態進行に関与するHLAアリルの探索 (2016)
  • Author(s): 近田 貴敬, Giang Van Tran, 村越 勇人, 田村 美子, 赤星 智寛, 久世 望, 阪井 恵子, 小柳 円, Kinh Van Nguyen, 滝口 雅文
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: 鹿児島県鹿児島市（かごしま県民交流センター）
  • Year and Date: 2016-11-24
• [Presentation] HIV-1と特異的CTLの相互適応 (2016)
  • Author(s): 赤星 智寛, 端本 昌夫, 村越 勇人, 近田 貴敬, 田村 美子, 潟永 博之, 岡 慎一, 滝口 雅文
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: 鹿児島県鹿児島市（かごしま県民交流センター）
  • Year and Date: 2016-11-24
• [Presentation] Impaired Effect of HLA-A*24:02-Associated Mutation on HLA-B*35:01-Associated HIV-1 Control (2016)
  • Author(s): Hayato Murakoshi, Tomohiro Akahoshi, Madoka Koyanagi, Takayuki Chikata, Katherine L James, Nozomi Kuse, Yoshiko Tamura, Sarah L Rowland-Jones, Shinichi Oka, Hiroyuki Gatanaga, and Masafumi Takiguchi
  • Organizer: HIVR4P 2016
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-10-17
  • Int'l Joint Research
• [Presentation] ベトナム人HIV-１感染者に見られるHIV-1感染制御に関与したHIV-1特異的細胞傷害性T細胞 (2015)
  • Author(s): 田村 美子, 村越 勇人, 丸山 理恵, Dung Hoai Nguyen, Giang Van Tran, 赤星 智寛, 久世 望, 近田 貴敬, 阪井 恵子, 小柳 円, 酒井 幸子, 岡 慎一, Kinh Van Nguyen, 滝口 雅文
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京都文京区（東京ドームホテル）
  • Year and Date: 2015-11-30
• [Presentation] ベトナム人HIV-1 subtype A/E 感染者コホートにおけるHLA-associated polymorphism の同定 (2015)
  • Author(s): 近田 貴敬, Giang Van Tran, Jonathan Carlson, 村越 勇人, Dung Hoai Nguyen, 田村 美子, 赤星 智寛, 久世 望, 阪井 恵子, 小柳 円, 酒井 幸子, Kyle Cobarrubias, 岡 慎一, Zabrina Brumme, Kinh Van Nguyen, 滝口 雅文
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京都文京区（東京ドームホテル）
  • Year and Date: 2015-11-30
• [Presentation] ベトナム人慢性HIV-1感染者におけるHIV-1特異的細胞傷害性T細胞の網羅的解析 (2015)
  • Author(s): 村越 勇人, 田村 美子, 丸山 理恵, Dung Hoai Nguyen, Giang Van Tran, 赤星 智寛, 久世 望, 阪井 恵子, 小柳 円, 酒井 幸子, 岡 慎一, Kinh Van Nguyen, 滝口 雅文
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京都文京区（東京ドームホテル）
  • Year and Date: 2015-11-30
• [Presentation] The impact of one amino-acid substitution outside the binding groove between HLA-C*03 subtypes in binding of HIV-1 peptide to the HLA molecules (2015)
  • Author(s): Takayuki Chikata, Hayato Murakoshi, Madoka Koyanagi, Tomohiro Akahoshi, and Masafumi Takiguchi
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 北海道札幌市 （札幌コンベンションセンター）
  • Year and Date: 2015-11-18
• [Presentation] An escape mutation selected by HIV-1-specific CTLs generates a novel CTL epitope (2015)
  • Author(s): Tomohiro Akahoshi, Madoka Koyanagi, Hayato Murakoshi, Nozomi Kuse, and Masafumi Takiguchi
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 北海道札幌市 （札幌コンベンションセンター）
  • Year and Date: 2015-11-18
• [Presentation] HIV-1-specific CD8+ T cells responsible for rapid AIDS progression in HIV-1-infected Japanese individuals carrying HLA-B*35:01 (2015)
  • Author(s): Hayato Murakoshi, Madoka Koyanagi, Tomohiro Akahoshi, Takayuki Chikata, and Masafumi Takiguchi
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 北海道札幌市 （札幌コンベンションセンター）
  • Year and Date: 2015-11-18
• [Presentation] 7.Identification of HLA-associated polymorphisms in a cohort of HIV-1 subtype A/E infection (2015)
  • Author(s): Tran Van Giang, Takayuki Chikata, Yoshiko Tamura, Tomohiro Akahoshi, Hayato Murakoshi, Nozomi Kuse, Shinichi Oka, Keiko Sakai, Nguyen Van Kinh, Masafumi Takiguchi
  • Organizer: IAS 2015
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] 1.Control of HIV-1 by cytotoxic T cells specific for multiple conserved epitopes (2015)
  • Author(s): Hayato Murakoshi, Tomohiro Akahoshi, Madoka Koyanagi, Takayuki Chikata, Takuya Naruto, Rie Maruyama, Yoshiko Tamura, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: IAS 2015
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [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
• [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