Identification of HIV-1-specific CTLs from HIV-1-infected individuals on long-term antiretroviral therapy (ART)

• Project/Area Number: 18K16181
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: CHIKATA TAKAYUKI 熊本大学, ヒトレトロウイルス学共同研究センター, 特任助教 (60749711)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HIV-1 / エピトープ / CTL / Shock and Kill / CD8 / ART / リザーバー / HIV-1潜伏感染細胞 / HIV-1特異的CTL / 抗レトロウイルス療法 / HIV感染症根治 / CTL反応 / HIV-1特異的T細胞 / 潜伏感染細胞

Outline of Final Research Achievements

We isolated PBMCs from HIV-1-infected Japanese individuals on long-term antiretroviral therapy (ART), and analyzed the CTL responses to 13 epitopes that were already demonstrated as the protective epitopes in HIV-1 infection by IFN-g ELISPOT assay. Although the number of the spot numbers were reduced compared with the result of chronic phase, CTL responses were detected in 13 out of 18 individuals （>100 SFU / 1,000,000 PBMC）. On the other hand, we synthesized the HLA tetramer for the epitopes that were not observed the CTL responses by ELISPOT. Finally, we could detect the population of HIV-1 specific CTLs using by tetramer staining. Our results confirmed that HIV-1 specific T cells remained after long-term ART. This suggests that we can induce and expand these protective epitope specific CTLs to eliminate HIV-1 infected cells in Shock and Kill strategy.

Academic Significance and Societal Importance of the Research Achievements

これまでに我々が同定したCTLは、日本人HIV-1感染者体内の感染細胞を認識し効果的に殺傷することのできると期待され、Shock and Killによるリザーバー排除の行う場合の有用なCTLの候補である。本研究によって抗レトロウイルス療法（ART）開始後数年が経っていてもHIV-1特異的メモリーT細胞が残存していることが確認された。この結果は今後日本でShock and Killが実施される際に、我々が以前同定したHIV-1増殖抑制能を有するCTLを標的として、誘導を試みることができる可能性を示唆している。

Research Products

• [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] 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] 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] 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