Elucidation of the effect of HCV propagationa and IFN sensitivity by amino acid substitution in interferon sensitivity-determining region.

• Project/Area Number: 26860309
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases (2014, 2016-2017); Yokohama City University (2015)
• Principal Investigator: SUGIYAMA Ryuichi 国立感染症研究所, ウイルス第二部, 研究員 (70714476)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: C型肝炎ウイルス / NS5A / インターフェロン / 薬剤感受性

Outline of Final Research Achievements

To assess the involvement of ISDR in the HCV life cycle and to clarify the molecular mechanisms influencing IFN susceptibility, we used recombinant JFH-1 viruses with NS5A of the genotype 1b Con1 strain (JFH1/5ACon1) and with NS5A ISDR containing 7 amino acid substitutions (JFH1/5ACon1/i-7mut), and compared the virus propagation and the induction of ISGs. By transfecting RNAs of these strains into cells, we found that the efficiency of infectious virus production of JFH1/5ACon1/i-7mut was attenuated compared with JFH1/5ACon1. After transfecting RNA into cells, the mRNA expression of ISGs was sufficiently induced by IFN treatment in JFH1/5ACon1/i-7mut-transfected but not in JFH1/5ACon1-transfected cells. These data suggested that the NS5A-mediated inhibition of ISG induction was deteriorated by amino acid substitutions in the ISDR. These observations explain the strain-specific evasion of IFN signaling by HCV.

Research Products

• [Journal Article] Evaluation of Heating Conditions for Inactivation of Hepatitis E Virus Genotypes 3 and 4. (2018)
  • Author(s): IMAGAWA T, SUGIYAMA R, SHIOTA T, LI TC, YOSHIZAKI S, WAKITA T, AND ISHII K.
  • Journal Title: Journal of Food Protection Volume: 81(6) Issue: 6 Pages: 947-952
  • DOI: 10.4315/0362-028x.jfp-17-290
  • Peer Reviewed / Open Access
• [Journal Article] Interferon sensitivity-determining region of hepatitis C virus influences virus production and interferon signaling (2017)
  • Author(s): Sugiyama R., Murayama A., Nitta S., Yamada N., Tasaka-Fujita M., Masaki T., Aly H. H., Shiina M., Ryo A., Ishii K., Wakita T. and Kato T.
  • Journal Title: Oncotarget Volume: 9 Issue: 5 Pages: 5627-5640
  • DOI: 10.18632/oncotarget.23562
  • Peer Reviewed / Open Access
• [Journal Article] Resistance mutations of hepatitis B virus in entecavir-refractory patients (2017)
  • Author(s): Yamada Norie、Sugiyama Ryuichi、Nitta Sayuri、Murayama Asako、Kobayashi Minoru、Okuse Chiaki、Suzuki Michihiro、Yasuda Kiyomi、Yotsuyanagi Hiroshi、Moriya Kyoji、Koike Kazuhiko、Wakita Takaji、Kato Takanobu
  • Journal Title: Hepatology Communications Volume: 1 Issue: 2 Pages: 110-121
  • DOI: 10.1002/hep4.1022
  • Peer Reviewed / Open Access
• [Journal Article] Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents. (2016)
  • Author(s): Nitta S, Asahina Y, Matsuda M, Yamada N, Sugiyama R, Masaki T, Suzuki R, Kato N, Watanabe M, Wakita T, Kato T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34652-34652
  • DOI: 10.1038/srep34652
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ATP1B3 Modulates the Restriction of HIV-1 Production and NF-κB Activation by BST-2. (2016)
  • Author(s): Hironori Nishitsuji, Ryuichi Sugiyama, Makoto Abe and Hiroshi Takaku.
  • Journal Title: J Biol Chem. Volume: 291 (9) Issue: 9 Pages: 4754-4762
  • DOI: 10.1074/jbc.m115.679357
  • Peer Reviewed
• [Journal Article] Amino acid polymorphisms in hepatitis C virus core affect infectious virus production and major histocompatibility complex class I molecule expression (2015)
  • Author(s): Tasaka-Fujita M, Sugiyama N, Kang W, Masaki T, Murayama A, Yamada N, Sugiyama R, Tsukuda S, Watashi K, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 13994-14002
  • DOI: 10.1038/srep13994
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ZNF10 inhibits HIV-1 LTR activity through interaction with NF-κB and Sp1 binding motifs. (2015)
  • Author(s): Hironori Nishitsuji, Leila Sawada, Ryuichi Sugiyama and Hiroshi Takaku.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 15 Pages: 2019-2025
  • DOI: 10.1016/j.febslet.2015.06.013
  • Peer Reviewed / Open Access
• [Journal Article] A new role for PGA1 in inhibiting hepatitis C virus-IRES-mediated translation by targeting viral translation factors. (2015)
  • Author(s): Tsukimoto A, Sugiyama R, Abe M, Nishitsuji H, Shimizu Y, Shimotohno K, Kawai G, Takaku H.
  • Journal Title: Antiviral Res Volume: 117 Pages: 1-9
  • DOI: 10.1016/j.antiviral.2015.01.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] E型肝炎ウイルスに対する熱不活化条件の検討 (2017)
  • Author(s): 杉山 隆一，今川 稔文，塩田 智之，李 天成，吉崎 佐矢香，脇田 隆字，石井 孝司．
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Amino acid substitutions in IFN sensitivity-determining region of HCV-NS5A affect infectious virus production and ISG induction. (2016)
  • Author(s): Ryuichi Sugiyama, Nao Sugiyama, Asako Murayama, Megumi Tasaka-Fujita, Norie Yamada, Sayuri Nitta, Takahiro Masaki, Koji Ishii, Akihide Ryo, Takaji Wakita, Takanobu Kato.
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Kyoto, Japan.
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Amino acid substitutions in ISDR of HCV-NS5A affect infectious virus production and ISG induction. (2016)
  • Author(s): Ryuichi Sugiyama, Nao Sugiyama, Asako Murayama, Megumi Tasaka-Fujita, Norie Yamada, Sayuri Nitta, Takahiro Masaki, Akihide Ryo, Takaji Wakita, Takanobu Kato.
  • Organizer: 25th Conference of the Asian Pacific Association for the Study of the Libber
  • Place of Presentation: グランドプリンスホテル新高輪 (東京都港区)
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] NS5A-ISDRアミノ酸変異によるHCV増殖およびIFN感受性への影響. (2014)
  • Author(s): 杉山隆一，杉山奈央，村山麻子，藤田めぐみ，山田典栄，新田沙由梨，脇田隆字，加藤孝宣.
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Elucidation of the effect of HCV propagation by amino acid substitution in interferon sensitivity-determining region. (2014)
  • Author(s): Sugiyama R, Sugiyaam N, Murayama A, Tasaka-Fujita M, Masaki T, Wakita T, Kato T.
  • Organizer: 21th International Symposium on Hepatitis C virus and Related Viruses.
  • Place of Presentation: Banff, Cnada.
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] NS5A-ISDRアミノ酸変異がHCV増殖に与える影響の解析. (2014)
  • Author(s): 杉山隆一，杉山奈央，村山麻子，藤田めぐみ，山田典栄，脇田隆字，加藤孝宣.
  • Organizer: 第24回抗ウイルス療法研究会総会
  • Place of Presentation: 山梨
  • Year and Date: 2014-05-07 – 2014-05-09