Estimation of structural and statistical sectors of HV-1 Env trimer by random matrix theory

• Project/Area Number: 16K08824
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Yokoyama Masaru 国立感染症研究所, 病原体ゲノム解析研究センター, 主任研究官 (70296028)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HIV-1 / エンベロープ / 揺らぎ / 統計的カップリング行列 / ランダム行列理論 / セクター / スペクトラルクラスタリング / 分子・構造

Outline of Final Research Achievements

To clarify the mechanism of the neutralizing antibody escape and the origin of functional constraints in the evolution of HIV-1 Env, we estimated the structural and statistical sectors by random matrix theory. One of the structural sectors contained the V3 tip and the adjacent protomer V1/V2. The result suggests that masking of the neutralizing epitope of the anti-V3 antibody is controlled by the correlation motion with the adjacent protomer V1/V2. We estimated the statistical sector located in the C-C loop in HIV-1 Env. This statistical sector would be intolerant of mutations in order to maintain structural stability.

Academic Significance and Societal Importance of the Research Achievements

本研究により、HIV-1 Env三量体のプロトマー間での相関運動による中和抗体逃避機構が明らかになった。この研究成果は、タンパク質構造に基づく抗原デザインや抗ウイルス薬による中和感受性の制御を可能にする。また、HIV-1 Envに変異を許容し難い進化セクターがあることを見出した。HIV-1は易変異性ウイルスであり、これまでEnvで変異を許容し難い部位の報告は無い。この進化セクターは新たな治療標的になると考えられる。

Research Products

• [Journal Article] Concomitant enhancement of HIV-1 replication potential and neutralization-resistance in concert with three adaptive mutations in Env V1/C2/C4 domains. (2019)
  • Author(s): Doi N, Yokoyama M, Koma T, Kotani O, Sato H, Adachi A, Nomaguchi M.
  • Journal Title: Frontiers in Microbiology Volume: 10 Pages: 2-2
  • DOI: 10.3389/fmicb.2019.00002
  • NAID: 120006937678
  • Peer Reviewed / Open Access
• [Journal Article] Intracerebral inoculation of mouse-passaged Saffold virus type 3 affects cerebellar development in neonatal mice. (2018)
  • Author(s): Kotani O, Suzuki T, Yokoyama M, Iwata-Yoshikawa N, Nakajima N, Sato H, Hasegawa H, Taguchi F, Shimizu H, Nagata N.
  • Journal Title: Journal of Virology Volume: pii: JVI. Pages: 10007-10021
  • DOI: 10.1128/jvi.00864-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development. (2017)
  • Author(s): Chutiwitoonchai N, Mano T, Kakisaka M, Sato H, Kondoh Y, Osada H, Kotani O, Yokoyama M, Sato H, Aida Y
  • Journal Title: Virology Volume: 507 Pages: 32-39
  • DOI: 10.1016/j.virol.2017.04.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deletion of a 197-Amino-Acid Region in the N-Terminal Domain of Spike Protein Attenuates Porcine Epidemic Diarrhea Virus in Piglets (2017)
  • Author(s): Hou Yixuan、Lin Chun-Ming、Yokoyama Masaru、Yount Boyd L.、Marthaler Douglas、Douglas Arianna L.、Ghimire Shristi、Qin Yibin、Baric Ralph S.、Saif Linda J.、Wang Qiuhong
  • Journal Title: Journal of Virology Volume: 91
  • DOI: 10.1128/jvi.00227-17
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Proposal for a Structural Model of the Feline Calicivirus Protease Bound to the Substrate Peptide under Physiological Conditions (2017)
  • Author(s): Yokoyama Masaru、Oka Tomoichiro、Takagi Hirotaka、Kojima Hirotatsu、Okabe Takayoshi、Nagano Tetsuo、Tohya Yukinobu、Sato Hironori
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 1-12
  • DOI: 10.3389/fmicb.2017.01383
  • Peer Reviewed / Open Access
• [Journal Article] Production of HIV-1 vif mRNA Is Modulated by Natural Nucleotide Variations and SLSA1 RNA Structure in SA1D2prox Genomic Region (2017)
  • Author(s): Nomaguchi Masako、Doi Naoya、Yoshida Tomoya、Koma Takaaki、Adachi Shun、Ode Hirotaka、Iwatani Yasumasa、Yokoyama Masaru、Sato Hironori、Adachi Akio
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 2542-2542
  • DOI: 10.3389/fmicb.2017.02542
  • NAID: 120006937675
  • Peer Reviewed / Open Access
• [Journal Article] Molecular dynamics simulation of the influenza A(H3N2) hemagglutinin trimer reveals the structural basis for adaptive evolution of the recent epidemic clade 3C.2a (2017)
  • Author(s): Yokoyama M, Fujisaki S, Shirakura M, Watanabe S, Odagiri T, Ito K, Sato H
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 584-584
  • DOI: 10.3389/fmicb.2017.00584
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evolutionary constraints on the norovirus pandemic variant GII.4_2006b over the five-year persistence in Japan (2017)
  • Author(s): Sato H, Yokoyama M, Nakamura H, Oka T, Katayama K, Takeda N, Noda M, Tanaka T, Motomura K
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 410-410
  • DOI: 10.3389/fmicb.2017.00410
  • Peer Reviewed / Open Access
• [Journal Article] Critical Contribution of Tyr15 in the HIV-1 Integrase (IN) in Facilitating IN Assembly and Nonenzymatic Function through the IN Precursor Form with Reverse Transcriptase. (2017)
  • Author(s): Takahata T, Takeda E, Tobiume M, Tokunaga K, Yokoyama M, Huang YL, Hasegawa A, Shioda T, Sato H, Kannagi M, Masuda T.
  • Journal Title: Journal of Virology Volume: 91
  • DOI: 10.1128/jvi.02003-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SL1 revisited: functional analysis of the structure and conformation of HIV-1 genome RNA. (2016)
  • Author(s): Sakuragi S, Yokoyama M, Shioda T, Sato H, Sakuragi JI.
  • Journal Title: Retrovirology. Volume: 13 Pages: 79-79
  • DOI: 10.1186/s12977-016-0310-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enhanced antibody-mediated neutralization of HIV-1 variants that are resistant to fusion inhibitors (2016)
  • Author(s): Alam, M., Kuwata, T., Shimura, K., Yokoyama, M., Ramirez Valdez, K. P., Tanaka, K., Maruta, Y., Oishi, S., Fujii, N., Sato, H., Matsuoka M. and Matsushita S.
  • Journal Title: Retrovirology Volume: 13 Pages: 70-70
  • DOI: 10.1186/s12977-016-0304-7
  • NAID: 120005973385
  • Peer Reviewed / Open Access
• [Journal Article] Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells (2016)
  • Author(s): Haga K, Fujimoto A, Takai-Todaka R , Miki M, Doan YH, Murakami K, Yokoyama M, Murata K, Nakanishi A, & Katayama K
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 113
  • DOI: 10.1073/pnas.1605575113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased HIV-1 Sensitivity to Neutralizing Antibodies by Mutations in The Env V3-Coding Region for Resistance to CXCR4 Antagonists (2016)
  • Author(s): Hikichi Y, Yokoyama M, Takemura T, Fujino M, Kumakura S, Maeda Y, Yamamoto N, Sato H, Matano T, Murakami T
  • Journal Title: J Gen Virol Volume: 97 Pages: 2427-2427
  • DOI: 10.1099/jgv.0.000536
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular Mechanism of HIV-1 Vpr for Binding to Importin-α. (2016)
  • Author(s): Miyatake H., Sanjoh A., Murakami T., Murakami H., Matsuda G., Hagiwara K., Yokoyama M., Sato H., Miyamoto Y., Dohmae N., Aida Y.
  • Journal Title: Journal of Molecular Biology Volume: 428 Pages: 2744-2757
  • DOI: 10.1016/j.jmb.2016.05.003
  • Peer Reviewed
• [Journal Article] Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by randam mutagenesis. (2016)
  • Author(s): Sultana, T., Nakayama, E.E., Tobita, S., Yokoyama, M., Seki, Y., Saito, A., Nomaguchi, M., Adachi, A., Akari, H., Sato, H., and Shioda, T.
  • Journal Title: J Gen Virol. Volume: 97 Pages: 963-976
  • DOI: 10.1099/jgv.0.000408
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 1.Role for the Gag-CA linker domain in the late HIV-1 replication phase (2018)
  • Author(s): Koma T，Kotani O，Doi N，Miyakawa K，Ryo A，Yokoyama M，Sato H，Adachi A，Nomaguchi M
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 網羅的 Env 標的阻害剤ライブラリーの構築-3 (2018)
  • Author(s): 原田恵嘉、野村 渉、鳴海哲夫、横山 勝、前田賢次、竹内怜音、紺野奇重、引地優太、佐藤裕徳、玉村啓和、俣野哲朗、吉村和久
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] 3.HIV-1 エンベロープ三量体における中和感受性に関連する構造とゆらぎ (2018)
  • Author(s): 横山 勝，佐藤裕徳
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] 4.Characterization of novel HIV-1 inhibitors targeting Gag-TSG101 interaction (2018)
  • Author(s): Siarot Lowela，Chutiwitoonchai Nopporn，佐藤洋隆，Chang Hao，小谷 治，横山 勝，佐藤裕徳，藤野真之，村上 勉，近藤恭光，本田香，長田裕之，上田一樹，伊藤嘉浩，青野俊裕，児玉栄一，黒田和道，武井正美，間 陽子
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] 5.A proposal of molecular dynamics based structural models of the Pr55Gag precursor of HIV-1 (2018)
  • Author(s): Kotani O，Yokoyama M，Ono A，Sato H
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] タンパク質構造情報を用いたインフルエンザウイルス・ヘマグルチニンの受容体指向性解析 (2017)
  • Author(s): 奥田 萌、横山 勝、佐藤裕徳、由良 敬
  • Organizer: 第6回日本生物物理学会関東支部会
  • Place of Presentation: 早稲田大学TWIns（東京都新宿区）
  • Year and Date: 2017-03-13
• [Presentation] HIVの細胞侵入を阻害するオレアノール酸誘導体の構造活性相関研究 (2017)
  • Author(s): 荻原香澄、引地優太、原田恵嘉、横山 勝、加藤由奈、佐藤浩平、間瀬暢之、吉村和久、鳴海哲夫
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] Structural sectors that are contributed to neutralization escape in HIV-1 envelope glycoprotein trimer (2017)
  • Author(s): 横山 勝、佐藤裕徳
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Analysis of mechanism of action of antivirals targeting HIV-1 Gag p6 (2017)
  • Author(s): 小谷 治、横山 勝、Loela Siarot、佐藤洋隆、Nopporn Chutiwitoonchai、間 陽子、佐藤裕徳
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Discovery of novel bifunctional entry inhibitors of HIV-1 using structure-based in silico screening (2017)
  • Author(s): Shigeyoshi Harada, Masaru Yokoyama, Kasumi Ogihara, Yuta Hikichi, Hironori Sato, Tetsuo Narumi, Tetsuro Matano, Kazuhisa Yoshimura
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] HIV-1インテグラーゼ非酵素的機能の分子基盤 (2017)
  • Author(s): 増田貴夫、高畑辰郎、黄 渝倫、王 寶れい、長谷川温彦、徳永研三、飛梅 実、塩田達夫、武田英里、俣野哲朗、横山 勝、河合剛太、佐藤裕徳、神奈木真理
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] 網羅的Env標的阻害剤ライブラリーの構築-2 (2017)
  • Author(s): 原田恵嘉、野村 渉、鳴海哲夫、横山 勝、前田賢次、林 宏典、紺野奇重、引地優太、佐藤裕徳、玉村啓和、俣野哲朗、吉村和久
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] HIV-1 エンベロープ三量体における中和抗体逃避機構の解析 (2017)
  • Author(s): 横山 勝、佐藤裕徳
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] 分子動力学計算によるHIV-1 エンベロープ三量体の構造セクターの解析 (2017)
  • Author(s): 横山 勝、佐藤裕徳
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 分子動力学計算を用いた抗HIVウイルス物質の作用機構解析 (2017)
  • Author(s): 小谷 治、横山 勝、Lowela Siarot、佐藤洋隆、Nopporn Chutiwitoonchai、間 陽子、佐藤裕徳
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] HIV-1 Env三量体における制限された構造ゆらぎ (2016)
  • Author(s): 横山 勝、奥田 萌、中村浩美、小谷 治、由良 敬、佐藤裕徳
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 網羅的Env標的阻害剤ライブラリーの構築-1 (2016)
  • Author(s): 原田恵嘉、野村渉、鳴海哲夫、横山 勝、前田賢次、林宏典、荻原香澄、石田有佑、引地優太、佐藤裕徳、玉村啓和、俣野哲朗、吉村和久
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2016-11-24
• [Presentation] HIV envelopeの構造と動的性質 (2016)
  • Author(s): 横山 勝
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2016-11-24
• [Presentation] ノロウイルスカプシドにおける構造ゆらぎと相関運動 (2016)
  • Author(s): 横山 勝、奥田 萌、中村浩美、小谷 治、由良 敬、佐藤裕徳
  • 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] エンテロウイルス粒子形成を制御するカプシド蛋白質機能領域の予測 (2016)
  • Author(s): 小谷治、横山勝、佐藤裕徳
  • 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] Structural Fluctuations and Correlated Motions in Norovirus Capsid Oligomer (2016)
  • Author(s): Yokoyama M, Okuda M, Nakamura H, Kotani O, Yura K, Sato H
  • Organizer: The 6th International Calicivirus Conference
  • Place of Presentation: Savannah （USA）
  • Year and Date: 2016-10-10
  • Int'l Joint Research
• [Presentation] ヒト免疫不全ウイルス1型（HIV-1) Gag と宿主因子TSG101との相互作用を標的とする新規HIV薬の開発 (2016)
  • Author(s): Lowela Siarot、佐藤洋隆、Nopporn Chutiwitoonchai、小谷 治、横山 勝、佐藤裕徳、本田香織、近藤恭光、長田裕之、間 陽子
  • Organizer: 第159回日本獣医学会学術集会
  • Place of Presentation: 日本大学生物資源科学部（神奈川県藤沢市）
  • Year and Date: 2016-09-06
• [Presentation] Molecular mechanism of inhibition by a new compound DP2392-E10 against influenza virus replication (2016)
  • Author(s): CHUTIWITOONCHAI N, KAKISAKA M, MANO T, SATO H, KOTANI O, YOKOYAMA M, SATO H, AIDA Y
  • Organizer: 第159回日本獣医学会学術集会
  • Place of Presentation: 日本大学生物資源科学部（神奈川県藤沢市）
  • Year and Date: 2016-09-06