Association between cell-death induction and pathogenesis in early phase of HIV infection in humanized mice

• Project/Area Number: 17K08800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Terahara Kazutaka 国立感染症研究所, 免疫部, 主任研究官 (50469954)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV / T細胞 / ヒト化マウス / 細胞死 / アポトーシス / パイロトーシス / ネクロプトーシス / CD4陽性T細胞 / ナイーブ / メモリー / 休止期 / 潜伏感染 / Flt3-L / GM-CSF / 制御性T細胞 / Th17

Outline of Final Research Achievements

Although transient loss of CD4 T cells occurs during early HIV infection, it remains unclear the characteristics of induced cell death and their relevance to immunopathogenesis. In this study, CD4 T-cell death was characterized during the early phase of HIV-infected humanized mice. As a result, CD4 T-cell death was significantly induced at 3 days post-infection in the spleen, and the main body of induced CD4 T-cell death was non-apoptotic cell death including pyroptosis and necroptosis but not apoptosis. These results suggest a relevance between non-apoptotic CD4 T-cell death and immunopathogenesis such as induction of inflammation.

Academic Significance and Societal Importance of the Research Achievements

現在世界的に行われている抗HIV療法は、ウイルス複製を抑え込みながら細胞死を抑制するのと同時に、宿主本来の免疫恒常性によってCD4 T細胞数の回復を可能にする。そして、さらなる効果的な治療戦略として、感染早期に誘導される細胞死を防ぐ手段も提案されている。しかしながら、どのような様式の細胞死が誘導されるのかについては明らかになっていない。したがって、本研究で得られた知見は臨床応用に向けた論理基盤を確立する上で意義深いものと考えられる。

Research Products

• [Journal Article] A CCR5+ memory subset within HIV-1-infected primary resting CD4+ T cells is permissive for replication-competent, latently infected viruses in vitro (2019)
  • Author(s): Terahara Kazutaka、Iwabuchi Ryutaro、Hosokawa Masahito、Nishikawa Yohei、Takeyama Haruko、Takahashi Yoshimasa、Tsunetsugu-Yokota Yasuko
  • Journal Title: BMC Research Notes Volume: 12 Issue: 1 Pages: 242-242
  • DOI: 10.1186/s13104-019-4281-5
  • Peer Reviewed / Open Access
• [Journal Article] Introduction of human Flt3-L and GM-CSF into humanized mice enhances the reconstitution and maturation of myeloid dendritic cells and the development of Foxp3+CD4+ T cells (2018)
  • Author(s): Iwabuchi R, Ikeno S, Kobayashi-Ishihara M, Takeyama H, Ato M, Tsunetsugu-Yokota Y, Terahara K
  • Journal Title: Front. Immunol. Volume: 9 Pages: 1042-1042
  • DOI: 10.3389/fimmu.2018.01042
  • Peer Reviewed / Open Access
• [Journal Article] HIV LTR-driven antisense RNA by itself has regulatory function and may curtail virus reactivation from latency (2018)
  • Author(s): Kobayashi-Ishihara M, Terahara K, Martinez JP, Yamagishi M, Iwabuchi R, Brander C, Ato M, Watanabe T, Meyerhans A, Tsunetsugu-Yokota Y
  • Journal Title: Front. Microbiol. Volume: 9 Pages: 1066-1066
  • DOI: 10.3389/fmicb.2018.01066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Characterization of human CD14low DC-like cells in lymphoid tissues using a humanized mouse model (2019)
  • Author(s): Iwabuchi R, Terahara K, Takahashi Y, Tsunetsugu-Yokota Y
  • Organizer: 第48回日本免疫学会総会・学術集会
• [Presentation] ヒト化マウスモデルを用いたHIV-1感染初期に誘導されるCD4陽性T細胞死の性状解析 (2019)
  • Author(s): 佐藤雄志、寺原和孝、 岩渕龍太郎、森川裕子、横田恭子
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] Preferential entry of CCR5-tropic HIV-1 over CXCR4-tropic HIV-1 into resting CCR5+CXCR4+ memory CD4+ T cells (2018)
  • Author(s): Terahara K, Iwabuchi R, Hosokawa M, Takeyama H, Tsunetsugu-Yokota Y
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Human GM-CSF and Flt3-L induce reconstitution and maturation of human myeloid dendritic cells in humanized mice. (2017)
  • Author(s): Iwabuchi R., Terahara K., Ishihara-Kobayashi M., Ato M., Tsunetsugu-Yokota Y.
  • Organizer: 第47回日本免疫学会総会・学術集会