Elcidating the regulatory mechanisms of intracellular level and function of HIV-1 Vif

• Project/Area Number: 16K08807
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kyoto University
• Principal Investigator: Shindo Keisuke 京都大学, 医学研究科, 特定病院助教 (10602344)
• Project Period (FY): 2016-04-01 – 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 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV-1 / Vif / CBF-beta / PP2A / MDM2 / anti-HIV drug / cell cycle arrest / ubiquitination / ubiquitin / Viral infectivity factor / ユビキチン / プロテアソーム / タンパク間相互作用 / ウイルス / 蛋白質 / 発現制御 / 感染症

Outline of Final Research Achievements

I have made two major achievements in the research on HIV-1 Vif.
First, I have elucidated that CBF-beta maintains intracellular levels of Vif protein mainly by suppressing MDM2-meidated degradation of Vif, suggesting higher probability of success for developing a new anti-HIV-1 drug that prevents interaction between Vif and CBF-beta.
Second, I have proposed and proved that HIV-1 Vif triggers G2 cell cycle arrest by ubiquitinating and promoting degradation of PP2A-B56 family proteins. These contribute to elucidate not only mechanisms of pathogenesis and replication augmentation of HIV-1, but also general regulation mechanisms of cell cycle.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果の学術的意義としては、HIV-1感染症の新規治療薬の開発を支持するものと、病原性発揮や感染性増強のメカニズムを明らかにするものがあげられる。既存のすべてのHIV-1感染症治療薬に対して、それに耐性を示すウイルス変異が同定されている。VifはHIV-1 の感染に必須のウイルス蛋白でありながら、その機能発現には決まった宿主蛋白との相互作用が必須であり、そこを標的とする抗ウイルス薬に対して生じた耐性変異はVif機能を失うことが予想され、薬剤耐性ウイルスを生じないと考えられる。

Research Products

• [Journal Article] Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest (2020)
  • Author(s): Nagata Kayoko、Shindo Keisuke、Matsui Yusuke、Shirakawa Kotaro、Takaori-Kondo Akifumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 527 Issue: 1 Pages: 257-263
  • DOI: 10.1016/j.bbrc.2020.04.123
  • NAID: 120006865708
  • Peer Reviewed
• [Journal Article] Core binding factor beta protects HIV-1, type 1 accessory protein viral infectivity factor from MDM2-mediated degradation (2016)
  • Author(s): Yusuke Matsui, Keisuke Shindo, Kayoko Nagata, Noriyoshi Yoshinaga, Kotaro Shirakawa, Masayuki Kobayashi and Akifumi Takaori-Kondo
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 48 Pages: 24892-24899
  • DOI: 10.1074/jbc.m116.734673
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Examining HIV-1 Vif determinants for inducing the cell cycle arrest (2018)
  • Author(s): Kayoko Nagata, Keisuke Shindo, Akifumi Takaori-Kondo
  • Organizer: Annual Meeting of the Japanese Society for Virology
• [Presentation] The roles of PP2A degradation in HIV-1 Vif-mediated cell cycle arrest (2017)
  • Author(s): Kayoko Nagata, Keisuke Shindo, Akifumi Takaori-Kondo
  • Organizer: Cold Spring Harbor Meeting on Retroviruses
  • Int'l Joint Research
• [Presentation] PP2A-B56delta degradation is crucial for HIV-1 Vif-mediated cell cycle arrest (2017)
  • Author(s): Kayoko Nagata, Keisuke Shindo, Akifumi Takaori-Kondo
  • Organizer: 日本ウイルス学会
• [Presentation] Ezamining three models for Vif-mediated cell cycle arrest (2016)
  • Author(s): Kayoko Nagata, Keisuke Shindo, Yusuke Matsui and Akifumi Takaori-Kondo
  • Organizer: Cold Spring Harbor Meeting on Retroviruses
  • Place of Presentation: New York, USA
  • Year and Date: 2016-05-23
  • Int'l Joint Research