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Analysis of the functional regulation of HIV structural protein Gag

Research Project

Project/Area Number 19K07594
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionYokohama City University

Principal Investigator

MIYAKAWA Kei  横浜市立大学, 医学部, 准教授 (20580046)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords宿主-ウイルス相互作用 / ウイルス-宿主相互作用 / ヒト免疫不全ウイルス / 内因性免疫
Outline of Research at the Start

HIV構造蛋白質Gagは、ウイルス複製環全体に関わる重要な蛋白質であるにも関わらず、その詳細な機能調節機構は不明である。本研究では、複雑なGagの挙動を反映した独自のアッセイ系を用い、Gagを機能不全に導く蛋白質を探索し、宿主によるGag機能制御機構やヒトのもつ生体防御機構について解明する。また、Gagは他のウイルス蛋白質に比べ変異許容度が低いため、Gagを標的薬に対する耐性ウイルス出現リスクも相対的に低いと予想されている。そこで、これらの生細胞アッセイ系を用いてGagを機能不全に導く化合物を探索し、Gag標的薬の有用性を検証する。

Outline of Final Research Achievements

The type I interferon (IFN) response is a robust anti-viral response that induces the transcription of several IFN-stimulated genes (ISGs). However, the effects of ISGs, particularly on the HIV-1 Gag protein, remain largely unknown. In this study, we screened ISG-encoded proteins by bioluminescence resonance energy transfer to identify the host effectors that suppressed Gag function. Consequently, we identified the transmembrane protein MAL as a Gag-interacting ISG product. Expression of MAL substantially inhibited the production of HIV-1 particles, leading to the translocation, accumulation, and eventual lysosomal degradation of Gag in the host endosomal compartments. Notably, the antiviral activity of MAL was partially antagonized by the viral accessory protein Nef, as it interfered with the interaction between MAL and Gag. Therefore, this study reveals a previously unidentified antiviral function of MAL and its viral counteraction.

Academic Significance and Societal Importance of the Research Achievements

本研究では、タンパク質間相互作用を生細胞でリアルタイムに検出可能な実験系を用いて、ヒト免疫不全ウイルスを顕著に抑制する機能をもつヒトタンパク質を多数同定し、宿主の自然免疫応答機構、およびウイルスがそれを克服する作用機序を明らかにした。これまで知られていなかったウイルスタンパク質の新たな機能が明らかとなり、ヒトが本来有する抗ウイルス活性を利用したHIV-1感染症の新規治療法開発に将来的に寄与するものと考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2022 2021 2019

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] MAL inhibits the production of HIV-1 particles by sequestering Gag to intracellular endosomal compartments.2022

    • Author(s)
      Miyakawa K, Nishi M, Jeremiah SS, Morikawa Y, Ryo A
    • Journal Title

      Frontiers in virology

      Volume: 2 Pages: 836125-836125

    • DOI

      10.3389/fviro.2022.836125

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion.2021

    • Author(s)
      Jeremiah SS, Miyakawa K, Matsunaga S, Nishi M, Kudoh A, Takaoka A, Sawasaki T, Ryo A.
    • Journal Title

      Front Microbiol.

      Volume: 12 Pages: 643407-643407

    • DOI

      10.3389/fmicb.2021.643407

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation2019

    • Author(s)
      Miyakawa Kei、Matsunaga Satoko、Yokoyama Masaru、Nomaguchi Masako、Kimura Yayoi、Nishi Mayuko、Kimura Hirokazu、Sato Hironori、Hirano Hisashi、Tamura Tomohiko、Akari Hirofumi、Miura Tomoyuki、Adachi Akio、Sawasaki Tatsuya、Yamamoto Naoki、Ryo Akihide
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 1844-1844

    • DOI

      10.1038/s41467-019-09867-7

    • NAID

      120006949469

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Allosteric Regulation of HIV-1 Capsid Structure for Gag Assembly, Virion Production, and Viral Infectivity by a Disordered Interdomain Linker.2019

    • Author(s)
      2.Koma T, Kotani O, Miyakawa K, Ryo A, Yokoyama M, Doi N, Adachi A, Sato H, Nomaguchi M
    • Journal Title

      Journal of Virology

      Volume: 93 (17) Issue: 17

    • DOI

      10.1128/jvi.00381-19

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ウイルス-宿主タンパク質相互作用解析とその応用2021

    • Author(s)
      宮川 敬, 梁 明秀
    • Organizer
      第35回日本エイズ学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Identification of kinases that facilitate lentiviral evasion from the host antiviral system.2019

    • Author(s)
      Miyakawa K, Ryo A
    • Organizer
      The 20th Kumamoto AIDS Seminar
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] HIV-1カプシド “disorder” 領域の構造機能解析2019

    • Author(s)
      小谷治, 駒貴明, 宮川敬, 梁明秀, 横山勝, 土肥直哉, 足立昭夫, 野間口雅子, 佐藤裕徳
    • Organizer
      第33回日本エイズ学会学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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