The role of de novo CTLs in recognition of mutant viruses escaped from HLA-mediated immune pressure

• Project/Area Number: 16K19160
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Kumamoto University
• Principal Investigator: Akahoshi Tomohiro 熊本大学, エイズ学研究センター, 特定事業研究員 (10635783)
• Research Collaborator: GATANAGA Hiroyuki 国立国際医療研究センター, エイズ治療・研究開発センター
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: HIV-1 / CTL / HLAクラスⅠ関連変異 / エピトープ推定 / 変異エピトープ / ネオエピトープ / 変異特異的CTL / HLA関連多型 / 感染症 / ウイルス / 細胞・組織 / 免疫学

Outline of Final Research Achievements

In present study, we aimed to clarify to what extent HIV-1-specific CD8+ cytotoxic T cells (CTL) recognizing HLA-adapted escape mutants are induced in a cohort of chronically HIV-1-infeand Japanese individuals and whether they contribute to control of HIV-1 replication. Among mutant epitopes which were predicted based on cohort’s consensus viral sequence containing HLA-associated mutations, we focused on two epitopes in which mixture of wild type (WT) and mutant viruses and/or frequent selection and reversion of those viruses were longitudinally observed. In those epitopes, cross-reactive CTLs, which recognized both WT and mutant peptides, and mutant-specific CTLs were induced in HIV-1-infected individuals. These results indicated that de novo CTLs recognizing HLA-adapted escape mutants elicited in chronic phase of HIV-1 infection may contribute to control of HIV-1 infection.

Research Products

• [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] 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
• [Journal Article] HIV-1 control by NK cells via reduced interaction between KIR2DL2 and HLA-C*12:02/C*14:03 (2016)
  • Author(s): Lin Z, Kuroki K, Kuse N, Sun X, Akahoshi T, Qi Y, Chikata T, Naruto T, Koyanagi M, Murakoshi H, Gatanaga H, Oka S, Carrington M, Maenaka K, Takiguchi M.
  • Journal Title: Cell Rep. Volume: 17 (9) Issue: 9 Pages: 2210-2220
  • DOI: 10.1016/j.celrep.2016.10.075
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of a Single Escape Mutation on T Cell and HIV-1 Co-adaptation. (2016)
  • Author(s): Sun X, Shi Y, Akahoshi T, Fujiwara M, Gatanaga H, Schönbach C, Kuse N, Appay V, Gao GF, Oka S, Takiguchi M.
  • Journal Title: Cell Rep. Volume: 15 (10） Issue: 10 Pages: 2279-91
  • DOI: 10.1016/j.celrep.2016.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] HLA class I-mediated HIV-1 control in HIV-1 infection (2018)
  • Author(s): Masafumi Takiguchi, Hayato Murakoshi, Takayuki Chikata, Tomohiro Akahoshi, Nozomi Kuse, Zhansong Lin, Mary Carrington, Hiroyuki Gatanaga, and Shinichi Oka
  • Organizer: 20th International Conference on Emerging Infectious Diseases in the Pacific Rim/U.S.-Japan Cooperative Medical Sciences Program (Shenzhen, China)
  • Int'l Joint Research
• [Presentation] HLA class I-mediated HIV-1 control in Vietnamese infected with HIV-1 subtype A/E (2018)
  • Author(s): Masafumi Takiguchi, Takayuki Chikata, Giang Van Tran, Hayato Murakoshi, Tomohiro Akahoshi, Ying Qi, Vivek Naranbhai, Nozomi Kuse, Yoshiko Tamura, Madoka Koyanagi, Sachiko Sakai, Dung Hoai Nguyen, Dung Thi Nguyen, Ha Thu Nguyen, Trung Vu Nguyen, Shinichi Oka, Maureen P. Martin, Mary Carrington, Keiko Sakai, et al.
  • Organizer: 20th International Conference on Emerging Infectious Diseases in the Pacific Rim/U.S.-Japan Cooperative Medical Sciences Program (Shenzhen, China)
  • 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（仙台）
• [Presentation] Effective priming of functional HIV-1-specific CD8+ T Cells from naive T cells using STING ligand (2017)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Takuya Yamamoto, Victor Appay, and Masafumi Takiguchi
  • Organizer: 第46回日本免疫学会学術集会（仙台）
• [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（東京）
• [Presentation] 複数の異なったHLA拘束性CTLによるRT135変異の選択とその相互作用 (2017)
  • Author(s): 赤星 智寛, 久世 望, 村越 勇人, 近田 貴敬, 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（東京）
• [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アリルおよびHLA関連HIV-1多型のエイズ病態進行に及ぼす影響 (2017)
  • Author(s): 近田 貴敬, Tran Van Giang, 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31回日本エイズ学会学術集会・総会（東京）
• [Presentation] STINGリガンドによるウイルス抑制機能の高いHIV-1特異的CD8陽性T細胞のプライミング (2017)
  • Author(s): 久世 望, Sun Xiaoming, 赤星 智寛, Lissina Anna, 山本 拓也, Appay Victor, 滝口 雅文
  • Organizer: 第31回日本エイズ学会学術集会・総会（東京）
• [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（大阪）
• [Presentation] Identification of a detrimental HLA haplotype and the effect of its associated HIV-1 mutations in HIV-1 subtype A/E-infected Vietnamese (2017)
  • Author(s): Takayuki Chikata, Hayato Murakoshi, Tomohiro Akahoshi, Nozomi Kuse, Yoshiko Tamura, Keiko Sakai, and Masafumi Takiguchi
  • Organizer: 第65回日本ウイルス学会学術集会（大阪）
• [Presentation] Control of HIV-1 by an HLA-B*52:01-HLA-C*12:02 protective haplotype (2017)
  • Author(s): Hayato Murakoshi, Takayuki Chikata, Madoka Koyanagi, Kazutaka Honda, Tomohiro Akahoshi, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • Int'l Joint Research
• [Presentation] STING ligand effectively prime functional HIV-1-specific CD8+ T Cells from naive T cells (2017)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Takuya Yamamoto, Victor Appay, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • Int'l Joint Research
• [Presentation] Generation of HIV-1 polymorphism at RT135 via coevolution of multiple HIV-1-specific T cells with HIV-1 (2017)
  • Author(s): Tomohiro Akahoshi, Nozomi Kuse, Hayato Murakoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • Int'l Joint Research
• [Presentation] HLA class I-mediated HIV-1 control in Vietnamese infected with HIV-1 subtype A/E (2017)
  • Author(s): Takayuki Chikata, Giang Van Tran, Hayato Murakoshi, Tomohiro Akahoshi, Nozomi Kuse, Ying Qi, Yoshiko Tamura, Madoka Koyanagi, Sachiko Sakai, Dung Hoai Nguyen, Dung Thi Nguyen, Ha Thu Nguyen, Trung Vu Nguyen, Shinichi Oka, Marry Carrington, Keiko Sakai, Kinh Van Nguyen, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • Int'l Joint Research
• [Presentation] The Effect of KIR Genes on HIV-1 Control in the Vietnamese Cohort (2017)
  • Author(s): Zhansong Lin, Takayuki Chikata, Giang Van Tran, Hayato Murakoshi, Tomohiro Akahoshi, Nozomi Kuse, Yoshiko Tamura, Madoka Koyanagi, Sachiko Sakai, Dung Hoai Nguyen, Dung Thi Nguyen, Ha Thu Nguyen, Trung Vu Nguyen, Keiko Sakai, Kinh Van Nguyen, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • Int'l Joint Research
• [Presentation] Analysis of conserved epitopes-specific and cross-reactive CTLs controlling HIV-1 in Japanese individuals (2017)
  • Author(s): Yu Zhang, Nozomi Kuse, Hayato Murakoshi, Tomohiro Akahoshi, Takayuki Chikata, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: 18th Kumamoto AIDS Seminar (Kumamoto, Japan)
  • 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, Katherine L James, Yoshiko Tamura, Nozomi Kuse, Xiaoming Sun, Hiroyuki Gatanaga, Sarah L Rowland-Jones, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: IAS 2017 (Paris, France)
  • Int'l Joint Research
• [Presentation] Effective priming of CD8+ T cells with ability to suppress HIV-1 replication using STING ligand (2017)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Ken J. Ishii, Takuya Yamamoto, Victor Appay, and Masafumi Takiguchi
  • Organizer: IAS 2017 (Paris, France)
  • Int'l Joint Research
• [Presentation] The effect of one amino acid difference outside of peptide binding groove of HLA-C molecules on NK cell function and HIV-1 control (2016)
  • Author(s): Zhansong Lin, Nozomi Kuse, Tomohiro Akahoshi, Kimiko Kuroki, Katsumi Maenaka, and Masafumi Takiguchi
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター(沖縄・宜野湾市)
  • Year and Date: 2016-12-05
• [Presentation] In vitro priming of HIV-1-specific CD8+ T cells from naive T cells (2016)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Takuya Yamamoto, Ken J. Ishii, Victor Appay, and Masafumi Takiguchi
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター(沖縄・宜野湾市)
  • Year and Date: 2016-12-05
• [Presentation] The effect of a single CTL escape -mutation on HIV-1 control by NK cell functions (2016)
  • Author(s): Zhansong Lin, Nozomi Kuse, Tomohiro Akahoshi, Kimiko Kuroki, Katsumi Maenaka, and Masafumi Takiguchi
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: かごしま県民交流センター(鹿児島県・鹿児島市)
  • Year and Date: 2016-11-24
• [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: かごしま県民交流センター(鹿児島県・鹿児島市)
  • 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: かごしま県民交流センター(鹿児島県・鹿児島市)
  • Year and Date: 2016-11-24
• [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: かごしま県民交流センター(鹿児島県・鹿児島市)
  • Year and Date: 2016-11-24
• [Presentation] Control of HIV-1 by NK cells via KIR-2DL2 and 2 HLA-C alleles (2016)
  • Author(s): Zhansong Lin, Kimiko Kuroki, Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Ying Qi, Takayuki Chikata, Takuya Naruto, Madoka Koyanagi, Hayato Murakoshi, Hiroyuki Gatanaga, Shinichi Oka, Mary Carrington, Katsumi Maenaka, Masafumi Takiguchi
  • Organizer: 2nd Kumamoto IRCMS International Symposium and 17th Kumamoto AIDS Seminar
  • Place of Presentation: くまもと県民交流館パレア(熊本県・熊本市)
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Contribution of HLA class I alleles to clinical outcome in HIV-1 subtype A/E infected Vietnamese individuals (2016)
  • Author(s): Takayuki Chikata, Giang Van Tran, Hayato Murakoshi, Yoshiko Tamura, Tomohiro Akahoshi, Nozomi Kuse, Madoka Koyanagi, Sachiko Sakai, Keiko Sakai, Kinh Van Nguyen, and Masafumi Takiguchi
  • Organizer: 2nd Kumamoto IRCMS International Symposium and 17th Kumamoto AIDS Seminar
  • Place of Presentation: くまもと県民交流館パレア(熊本県・熊本市)
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Co-evolution between HIV-1 escape mutant and HIV-1-specific T cells (2016)
  • Author(s): Tomohiro Akahoshi, Masao Hashimoto, Takayuki Chikata, Hayato Murakoshi, Nozomi Kuse, Yoshiko Tamura, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi
  • Organizer: 2nd Kumamoto IRCMS International Symposium and 17th Kumamoto AIDS Seminar
  • Place of Presentation: くまもと県民交流館パレア(熊本県・熊本市)
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Functional analysis of HIV-1-specific CD8+ T cells primed in vitro from naive T cells (2016)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Victor Appay, and Masafumi Takiguchi
  • Organizer: 2nd Kumamoto IRCMS International Symposium and 17th Kumamoto AIDS Seminar
  • Place of Presentation: くまもと県民交流館パレア(熊本県・熊本市)
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Contribution of HLA class I alleles to clinical outcome in HIV-1 subtype A/E infected Vietnamese individuals (2016)
  • Author(s): Takayuki Chikata, Giang Van Tran, Hayato Murakoshi, Yoshiko Tamura, Tomohiro Akahoshi, Nozomi Kuse, Keiko Sakai, Kinh Van Nguyen, and Masafumi Takiguchi
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター(北海道・札幌市)
  • Year and Date: 2016-10-23
• [Presentation] In Vitro Priming of HIV-1-specific CD8+ T Cells from Naive T Cells (2016)
  • Author(s): Nozomi Kuse, Xiaoming Sun, Tomohiro Akahoshi, Anna Lissina, Victor Appay, and Masafumi Takiguchi
  • Organizer: HIVR4P 2016
  • Place of Presentation: Sheraton Grand Chicago(Chicago, USA)
  • Year and Date: 2016-10-17
  • Int'l Joint Research
• [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: Sheraton Grand Chicago(Chicago, USA)
  • 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 研究業績
  • URL: http://www.caids.kumamoto-u.ac.jp/data/takiguchi/viral/gyouseki/gyousekitop.htm