Comprehensive identification of host factors which contribute to replication of herpes virus using genome editing

• Project/Area Number: 16K15280
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: The University of Tokyo
• Principal Investigator: Kawaguchi Yasushi 東京大学, 医科学研究所, 教授 (60292984)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ウイルス / HSV / ゲノム編集

Outline of Final Research Achievements

In this study, (i) we created platform for efficient screening of host factors responsible for HSV replication, by constructing reporter virus in which reporter gene products were incorporated into HSV virions. (ii) Using the reporter virus, several host factors which contribute to HSV replication were identified. Furthermore, we clarified that these host factors were important for intracellular transport of HSV. (iii) We demonstrated that host ESCRT-III machinery is used for HSV budding through the inner nuclear membrane, by analyzing host factors that contribute to viral particle formation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、HSVの増殖に必要な宿主因子を効率的にスクリーニングするためのプラットフォームを構築し、HSV増殖に必要な宿主因子を複数同定しただけでなく、長年にわたり未解明であったHSVカプシドの核外輸送の分子機構を解明した点で、学術的に高い意義を有していると考えられる。また、本研究成果によって構築したスクリーニング法は、HSV感染症に対する宿主細胞因子を標的とした創薬への応用に繋がることが期待される。

Research Products

• [Journal Article] ESCRT-III mediates budding across the inner nuclear membrane and regulates its integrity. (2018)
  • Author(s): Arii J, Watanabe M, Maeda F, Tokai-Nishizumi N, Chihara T, Miura M, Maruzuru Y, Koyanagi N, Kato A, Kawaguchi Y.
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 3379-3379
  • DOI: 10.1038/s41467-018-05889-9
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 VP22 Inhibits AIM2-Dependent Inflammasome Activation to Enable Efficient Viral Replication. (2018)
  • Author(s): Maruzuru Y, Ichinohe T, Sato R, Miyake K, Okano T, Suzuki T, Koshiba T, Koyanagi N, Tsuda S, Watanabe M, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: Cell Host Microbe. Volume: 23 Issue: 2 Pages: 254-265
  • DOI: 10.1016/j.chom.2017.12.014
  • Peer Reviewed / Open Access
• [Journal Article] Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis. (2017)
  • Author(s): Koyanagi N, Imai T, Shindo K, Sato A, Fujii W, Ichinohe T, Takemura N, Kakuta S, Uematsu S, Kiyono H, Maruzuru Y, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: J Clin Invest. Volume: 127 Issue: 10 Pages: 3784-3795
  • DOI: 10.1172/jci92931
  • Peer Reviewed / Open Access
• [Journal Article] Complete fusion of a transposon and herpesvirus created the Teratorn mobile element in medaka fish (2017)
  • Author(s): Inoue Yusuke、Saga Tomonori、Aikawa Takumi、Kumagai Masahiko、Shimada Atsuko、Kawaguchi Yasushi、Naruse Kiyoshi、Morishita Shinichi、Koga Akihiko、Takeda Hiroyuki
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 551-551
  • DOI: 10.1038/s41467-017-00527-2
  • NAID: 120006822516
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 Small Capsomere-Interacting Protein VP26 Regulates Nucleocapsid Maturation. (2017)
  • Author(s): Kobayashi R, Kato A, Sagara H, Watanabe M, Maruzuru Y, Koyanagi N, Arii J, Kawaguchi Y.
  • Journal Title: J Virol. Volume: 91 Issue: 18
  • DOI: 10.1128/jvi.01068-17
  • Peer Reviewed / Open Access
• [Journal Article] Herpes Simplex Virus 1 UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells. (2017)
  • Author(s): F. Maeda, J. Arii, Y. Hirohata, Y. Maruzuru, N. Koyanagi, A. Kato and Y. Kawaguchi.
  • Journal Title: J. Virol. Volume: 印刷中 Issue: 12
  • DOI: 10.1128/jvi.00271-17
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 2016 International meeting of the Global Virus Network (2017)
  • Author(s): Akkina Ramesh、Ellerbrok Heinz、Hall William、Hasegawa Hideki、Kawaguchi Yasushi、Kleanthous Harold、McSweegan Edward、Mercer Natalia、Romanowski Victor、Sawa Hirofumi、Vahlne Anders
  • Journal Title: Antiviral Research Volume: 142 Pages: 21-29
  • DOI: 10.1016/j.antiviral.2017.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A single amino acid substitution in HSV-1 UL31 at an inter-hexamer contact site abrogates primary envelopment and viral growth (2018)
  • Author(s): Jun Arii, Kosuke Takeshima, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Residues in α-helix 9 of HSV-1 UL31 is critical for interaction with UL25 and incorporation of capsid into vesicles in the perinuclear space (2018)
  • Author(s): Kosuke Takeshima, Jun Arii, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] A single amino acid substitution in herpes simplex virus 1 UL31 at an inter-hexamer contact site abrogates primary envelopment and viral growth (2018)
  • Author(s): Jun Arii, Kosuke Takeshima, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 43rd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Role of amino acid residues in the α-helix 9 of HSV-1 UL31 in its interaction with capsid proteins and nuclear egress (2018)
  • Author(s): Kosuke Takeshima, Jun Arii, Yuhei Maruzuru, Naoto Koyanagi, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 43rd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Novel Mechanisms for Immune Evasion by Herpes Simplex virus (2018)
  • Author(s): Yasushi Kawaguchi
  • Organizer: International Joint Forum on Infectious Disease Research 2018
  • Int'l Joint Research
• [Presentation] Inhibition of AIM2 inflammasome activation by an HSV-1 virion component enables efficient viral replication in vivo (2017)
  • Author(s): Yuhei Maruzuru, Takeshi Ichinohe, Naoto Koyanagi, Jun Arii, Akihisa Kato and Yasushi Kawaguchi
  • Organizer: 第31回ヘルペスウイルス研究会
• [Presentation] Evasion of AIM2-Dependent Inflamasome Activation by Herpes Simplex Virus 1 Virion Protein Enables Efficient Viral Replication In Vivo (2017)
  • Author(s): Yuhei Maruzuru, Takeshi Ichinohe, Naoto Koyanagi, Zhuoming Liu, Tomoko Ando, Jun Arii, Akihisa Kato, Yasushi Kawaguchi
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] 単純ヘルペスウイルスの宿主免疫回避機構 (2017)
  • Author(s): 川口 寧
  • Organizer: 日本生化学会北陸支部第35回大会
  • Invited
• [Presentation] Inhibition of AIM2 inflammasome activation by an HSV-1 virion component enables efficient viral replication in vivo (2017)
  • Author(s): Yuhei Maruzuru, Takeshi Ichinohe, Naoto Koyanagi, Jun Arii, Akihisa Kato and Yasushi Kawaguchi
  • Organizer: 42nd Annual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Novel Mechanisms for Immune Evasion by herpes simplex virus (2017)
  • Author(s): Yasushi Kawaguchi
  • Organizer: 24th East Asia Joint Symposium
  • Int'l Joint Research
• [Presentation] Investigation of a novel interaction between the endosomal sorting protein SNX3 and HSV-1 membrane proteins (2016)
  • Author(s): Akihisa Kato, Hayato Harima, Jun Arii, Yasushi Kawaguchi
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Endosomal sorting protein SNX3とHSV膜蛋白質の相互作用に関する解析 (2016)
  • Author(s): 加藤哲久, 播磨勇人, 有井潤, 川口寧
  • Organizer: 第30回ヘルペスウイルス研究会
  • Place of Presentation: セミナーハウス クロス・ウェーブ府中（東京都府中市）
  • Year and Date: 2016-06-16
• [Remarks] 東京大学医科学研究所 感染・免疫部門 ウイルス病態制御分野
  • URL: http://www.ims.u-tokyo.ac.jp/Kawaguchi-lab/KawaguchiLabTop.html