Development of a novel approach to induce cellular immune response for elimination of circulating HIV-1

• Project/Area Number: 20K07549
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: National Institute of Infectious Diseases (2022); Kumamoto University (2020-2021)
• Principal Investigator: Kuse Nozomi 国立感染症研究所, 治療薬・ワクチン開発研究センター, 主任研究官 (80710409)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV-1 / CTL / CD8陽性T細胞 / 逃避変異体 / プライミング / エピトープ / mutant / priming / STING / naive / protective epitope / 変異 / ナイーブ / メモリー / cART / 変異ウイルス / 細胞傷害性T細胞 / HLA

Outline of Research at the Start

潜伏HIV-1の排除に向けて、再活性化させたHIV-1を免疫力で排除するという戦略がエイズ完治療法の一つに提案されている。CTLを用いた方法では、感染者で効果的なCTLの誘導が必要であるが、長期治療感染者ではエフェクター細胞の消失、メモリー細胞の機能低下が見られる。
本研究では、STING活性化により、HIV-1感染者から国内の流行変異HIV-1を排除できるCTLの免疫応答を可能にする方法の確立を目指す。変異HIV-1も排除できる機能を持ったCTLをナイーブT細胞から新規誘導、メモリー細胞から再活性化により誘導する。
本研究の成果によって、エイズの完治療法に必要な免疫面での課題を解決できる。

Outline of Final Research Achievements

Induction of mutant-specific or cross-recognizing CTLs is critical for elimination of circulating HIV-1 in HIV-1-infected individuals. In this study, we investigated induction of HIV-1-specific CTLs with ability to recognize mutant virus from naive T cells using epitope restricted by HLA alleles, which is high prevalent alleles in Japanese individuals. We showed that HIV-1-specific CTLs carrying TCRs with ability to recognize circulating mutant viruses were elicited from naive T cells with STING activation. The study suggested that approach using STING activation would induce de novo HIV-1-specific CTLs with ability to recognize circulating HIV-1 from naive T cells and may contribute to development of effective T-cell vaccine or a functional cure for HIV-1.

Academic Significance and Societal Importance of the Research Achievements

薬剤治療で長期的にHIV-1を抑制できるようになったが、潜伏HIVまでは完全に排除できない。そのため再活性させたHIV-1をCTLなどの免疫力で排除するという戦略がエイズ完治療法の一つとして提案されている。一方でHIV-1感染者は様々な変異HIV-1に感染しているため、流行HIV-1を排除できる交差反応または変異特異的CTLの誘導がエイズ完治療法やワクチン開発に重要である。本研究ではSTING活性化により、国内に流行している変異ウイルスも認識できる機能を持ったCTLをナイーブT細胞から新規誘導できた。本研究の成果によって、エイズの完治療法に必要な免疫面での課題を解決できる可能性が示唆された。

Research Products

• [Journal Article] Immunological Control of HIV-1 Disease Progression by Rare Protective HLA Allele (2022)
  • Author(s): Zhang Yu、Chikata Takayuki、Kuse Nozomi、Murakoshi Hayato、Gatanaga Hiroyuki、Oka Shinichi、Takiguchi Masafumi
  • Journal Title: Journal of Virology Volume: 96 Issue: 22
  • DOI: 10.1128/jvi.01248-22
  • Peer Reviewed / Open Access
• [Journal Article] Control of HIV-1 Replication by CD8+ T Cells Specific for Two Novel Pol Protective Epitopes in HIV-1 Subtype A/E Infection. (2022)
  • Author(s): Nguyen HT, Kuse N, Zhang Y, Murakoshi H, Maeda Y, Tamura Y, Maruyama R, Tran GV, Nguyen TV, Nguyen KV, Oka S, Chikata T, Takiguchi M.
  • Journal Title: Journal of Virology Volume: 96 Issue: 19
  • DOI: 10.1128/jvi.00811-22
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Micropolymorphism Outside the Peptide Binding Groove in the Clinically Relevant Allele HLA-C*14 on T Cell Responses in HIV-1 Infection (2022)
  • Author(s): Chikata T, Paes W, Kuse N, Partridge T, Gatanaga H, Zhang Y, Kuroki K, Maenaka K, Ternette N, Oka S, Borrow P, Takiguchi M
  • Journal Title: Journal of Virology Volume: 96 Issue: 10
  • DOI: 10.1128/jvi.00432-22
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STING Ligand-Mediated Priming of Functional CD8+ T Cells Specific for HIV-1-Protective Epitopes from Naive T Cells (2021)
  • Author(s): Kuse Nozomi、Akahoshi Tomohiro、Takiguchi Masafumi
  • Journal Title: Journal of Virology Volume: 95 Issue: 16
  • DOI: 10.1128/jvi.00699-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8+ T Cells and Accumulation of HLA-Associated Escape Mutations (2020)
  • Author(s): Zhang Yu、Murakoshi Hayato、Chikata Takayuki、Akahoshi Tomohiro、Tran Giang Van、Nguyen Trung Vu、Gatanaga Hiroyuki、Nguyen Kinh Van、Oka Shinichi、Kuse Nozomi、Takiguchi Masafumi
  • Journal Title: Journal of Virology Volume: 95 Issue: 6
  • DOI: 10.1128/jvi.02061-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical effect of Pol escape mutations associated with detrimental allele HLA-C?15:05 on clinical outcome in HIV-1 subtype A/E infection (2020)
  • Author(s): Murakoshi Hayato、Chikata Takayuki、Akahoshi Tomohiro、Zou Chengcheng、Borghan Mohamed Ali、Van Tran Giang、Nguyen Trung Vu、Van Nguyen Kinh、Kuse Nozomi、Takiguchi Masafumi
  • Journal Title: AIDS Volume: 35 Issue: 1 Pages: 33-43
  • DOI: 10.1097/qad.0000000000002704
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics (2020)
  • Author(s): Akahoshi Tomohiro、Gatanaga Hiroyuki、Kuse Nozomi、Chikata Takayuki、Koyanagi Madoka、Ishizuka Naoki、Brumme Chanson J.、Murakoshi Hayato、Brumme Zabrina L.、Oka Shinichi、Takiguchi Masafumi
  • Journal Title: PLOS Pathogens Volume: 16 Issue: 12 Pages: e1009177-e1009177
  • DOI: 10.1371/journal.ppat.1009177
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1 (2020)
  • Author(s): Zhang Yu、Kuse Nozomi、Akahoshi Tomohiro、Chikata Takayuki、Gatanaga Hiroyuki、Oka Shinichi、Murakoshi Hayato、Takiguchi Masafumi
  • Journal Title: Journal of Virology Volume: 94 Issue: 19
  • DOI: 10.1128/jvi.01151-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8+ T-cell responses in vitro (2020)
  • Author(s): Papagno Laura、Kuse Nozomi、Lissina Anna、Gostick Emma、Price David A.、Appay Victor、Nicoli Francesco
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11620-11620
  • DOI: 10.1038/s41598-020-67704-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effective priming of functional CD8+ T cells specific for HIV protective epitopes from naïve T cells (2023)
  • Author(s): Nozomi Kuse
  • Organizer: Oxford-Kumamoto Universities Joint Annual Symposium
  • Int'l Joint Research
• [Presentation] Functional CD8+ T cells specific for HIV-1 protective epitopes primed with STING ligand (2021)
  • Author(s): Nozomi Kuse, Tomohiro Akahoshi, and Masafumi Takiguchi
  • Organizer: The 35th Annual Meeting of the Japanese Society for AIDS Research France-Japan Joint Symposium
  • Int'l Joint Research
• [Presentation] ナイーブT細胞からのconserved/プロテクティブエピトープ特異的CTLの誘導 (2020)
  • Author(s): 久世望, 赤星智寛, 滝口雅文
  • Organizer: 第34回日本エイズ学会学術集会・総会
• [Remarks] 熊本大学 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: https://kumamoto-u-jrchri.jp/takiguchi/default.html