Structure analysis of human herpesvirus 6 glycoprotein complex which is essential for the receptor binding

• Project/Area Number: 19K06512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Kobe University
• Principal Investigator: Nishimura Mitsuhiro 神戸大学, 医学研究科, 助教 (40510285)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); 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: ヒトヘルペスウイルス6 / X線結晶構造解析 / クライオ電子顕微鏡解析 / ヘルペスウイルス6 / 電子顕微鏡解析 / 相互作用解析

Outline of Research at the Start

ヒトヘルペスウイルス６（human herpesvirus 6; HHV-6）はヘルペスウイルス科に属し、ヒトに感染後生涯体内に潜伏し続ける病原ウイルスである。HHV-6には性状の異なるHHV-6AとHHV-6Bがあり、HHV-6Bは小児突発性発疹を引き起こすが、それらの感染および病原性発現機構については不明な点が多い。本研究ではHHV-6ウイルスの表面に発現する事で感染の鍵となっているgH/gL/gQ1/gQ2複合体について立体構造を決定し、その構造および機能を解明する。その成果はHHV-6感染機構の解明を推進し、またワクチンや阻害薬と言ったHHV-6感染に対する対処法の開発に繋がる。

Outline of Final Research Achievements

Human herpesvirus 6 (HHV-6) has a glycoprotein complex gH/gL/gQ1/gQ2 on the virion surface, and the complex plays an essential role on recognizing the host receptor CD134. The interaction between gH/gL/gQ1/gQ2 and CD134 is important for the infection, and hence the inhibition by antibodies results in neutralization. In this study the structure of gH/gL/gQ1/gQ2 and its interaction with CD134 or antibodies were analyzed. The affinity between gH/gL/gQ1/gQ2 and CD134 was revealed to be high enough to sense target cells. Inhibition of the molecular interaction by a neutralizing antibody was demonstrated. The overall shape of gH/gL/gQ1/gQ2 was visualized by electron microscopy, and biding locations of two neutralizing antibodies on the gH/gL/gQ1/gQ2 were also revealed. Protein crystals of gH/gL/gQ1/gQ2 with Fabs of neutralizing antibodies were obtained. X-ray diffraction measurement using the crystals resulted in a diffraction data at the maximum resolution 3.8 angstrom.

Academic Significance and Societal Importance of the Research Achievements

ヒトヘルペスウイルス6は全てのヒトが乳幼児期に感染するウイルスであり、生涯にわたり体内に潜伏感染し続けている病原体である。初感染時や再活性化時に脳炎を引き起こし得る危険性が知られており、未だ効果的な対処法は確立されていない。感染にはgH/gL/gQ1/gQ2と呼ばれる因子が必須の働きを担っているが、その立体構造や機能については未だに不明な点が多く残されている。本研究ではgH/gL/gQ1/gQ2の分子としての立体構造を解析するとともに、感染標的となる細胞で受容体となっているタンパク質との相互作用や、免疫系が作り出す中和抗体との相互作用の解析を行うことで、その機能についての知見を得た。

Research Products

• [Journal Article] Structural basis for the interaction of human herpesvirus 6B tetrameric glycoprotein complex with the cellular receptor, human CD134 (2020)
  • Author(s): Mitsuhiro Nishimura, Dian Novita Krisdianto, Takayuki Kato, Lidya Handayani Tjan, Bochao Wang, Aika Wakata, Anna Lystia Poetranto, Akiko Kawabata, Huamin Tang, Taiki Aoshi, Yasuko Mori
  • Journal Title: PLoS Pathogens Volume: in press
  • NAID: 120006878582
  • Peer Reviewed
• [Presentation] Molecular interaction of HHV-6B gH/gL/gQ1/gQ2 complex with the cellular receptor and neutralizing antibodies. (2019)
  • Author(s): Mitsuhiro Nishimura, Dian Novita Krisdianto, Bochao Wang, Aika Wakata, Anna Lystia Poetranto, Lidya Handayani Tjan, Takayuki Kato, Taiki Aoshi, Keiichi Namba, Yasuko Mori
  • Organizer: 11th International Conference on HHV-6 & 7
  • Int'l Joint Research
• [Presentation] Structure based analysis of human herpesvirus 6B glycoprotein complex with neutralizing antibodies (2019)
  • Author(s): Mitsuhiro Nishimura, Dian Novita Krisdianto, Zhenxiao Ren, Bochao Wang, Aika Wakata, Anna Lystia Poetranto, Lidya Handayani Tjan, Takayuki Kato, Taiki Aoshi, Keiichi Namba, Yasuko Mori
  • Organizer: 第 58回日本ウイルス学会学術集会