Analysis of mechanisms for suppressing interferon responsiveness by chronic hepatitis B virus infection

• Project/Area Number: 15K09002
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: TSUGE MASATAKA 広島大学, 自然科学研究支援開発センター, 助教 (50448263)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: B型肝炎ウイルス / 遺伝子発現 / インターフェロン / 治療抵抗性

Outline of Final Research Achievements

It is considered that many gene expressions are regulated by hepatitis B virus (HBV) infection and this regulation of gene expressions are different among infected HBV genotypes. Howevere, it has not been clarified the differences of regulation in gene expresions among HBV genotypes. In the present study, I analyzed gene expression profiles using human hepatocytes with or without HBV infection and then I also analyzed the association between HBV related proteins and the regulated genes via HBV infection. By gene expression analysis, it was identified that regulation levels in several gene expressions were different between HBV genotype A and C infection. And further analyses were indicated that transcription of one gene was regulated by HBx and HBs protein and the upregulation of this gene suppressed interferon responsiveness in human hepatocytes.

Research Products

• [Journal Article] Combinational use of (2018)
  • Author(s): Matsumoto A, Nishiguchi S, Enomoto H, Kang JH, Tanaka Y, Shinkai N, Kurosaki M, Enomoto M, Kanda T, Yokosuka O, Yatsuhashi H, Nagaoka S, Okuse C, Kagawa T, Mine T, Takaguchi K, Saito S, Hino K, Ikeda F, Sakisaka S, Morihara D, Miyase S, Tsuge M, Chayama K, Hiramatsu N, Suzuki Y, Murata K, Tanaka E
  • Journal Title: J Gastroenterol Volume: 53 Issue: 2 Pages: 247-257
  • DOI: 10.1007/s00535-017-1360-z
  • Peer Reviewed / Open Access
• [Journal Article] Development of a novel site-specific pegylated interferon beta for antiviral therapy for chronic hepatitis B. (2017)
  • Author(s): Tsuge M, Uchida T, Hiraga N, Kan H, Makokha GN, Abe-Chayama H, Miki D, Imamura M, Ochi H, Hayes CN, Shimozono R, Iwamura T, Narumi H, Suzuki T, Kainoh M, Taniguchi T, Chayama K.
  • Journal Title: Antimicrob Agents Chemother. Volume: 印刷中 Issue: 6 Pages: 61-61
  • DOI: 10.1128/aac.00183-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persistent loss of HBV markers in serum without cellular immunity by combination of PEG-IFN plus ETV therapy in humanized mice (2017)
  • Author(s): Uchida T, Imamura M, Hayes CN, Hiraga N, Kan H, Tsuge M, Abe-Chayama H, Zhang Y, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K
  • Journal Title: Antimicrob Agents Chemother Volume: 61 Issue: 9
  • DOI: 10.1128/aac.00725-17
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of humanized cDNA-uPA/SCID mice for the study of hepatitis B virus and hepatitis C virus virology. (2017)
  • Author(s): Uchida T, Imamura M, Kan H, Hiraga N, Hayes CN, Tsuge M, Abe-Chayama H, Aikata H, Makokha GN, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K.
  • Journal Title: J Gen Virol. Volume: 印刷中 Issue: 5 Pages: 1040-1047
  • DOI: 10.1099/jgv.0.000726
  • Peer Reviewed
• [Journal Article] The relationship between HBcrAg and HBV reinfection in HBV related post-liver transplantation patients. (2017)
  • Author(s): Urabe A, Imamura M, Tsuge M, Kan H, Fujino H, Fukuhara T, Masaki K, Kobayashi T, Ono A, Nakahara T, Kawaoka T, Hiramatsu A, Kawakami Y, Aikata H, Hayes CN, Maki N, Ohdan H, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 52 Issue: 3 Pages: 366-375
  • DOI: 10.1007/s00535-016-1240-y
  • Peer Reviewed / Open Access
• [Journal Article] The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study. (2017)
  • Author(s): Taida T., Arai M., Kanda T., Hige S., Ueno Y., Imazeki F., Izumi N., Tanaka E., Shinkai N., Yoshioka K., Nakamoto Y., Nishiguchi S., Tsuge M., Abe M., Sata M., Yatsuhashi H., Ido A., Kita K., Azemoto R., Kitsukawa Y., Goto N. and Yokosuka O.
  • Journal Title: Journal of Gastroenterology Volume: 52 Issue: 1 Pages: 113-122
  • DOI: 10.1007/s00535-016-1229-6
  • Peer Reviewed / Open Access
• [Journal Article] Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir andBMS-788329 combination therapy in human hepatocyte chimeric mice. (2016)
  • Author(s): Uchida T, Hiraga N, Imamura M, Yoshimi S, Kan H, Miyaki E, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Ellis JD, Chayama K.
  • Journal Title: Virus Res. Volume: 213 Issue: 1 Pages: 62-68
  • DOI: 10.1016/j.jinf.2015.09.038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. (2016)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Journal of Gastroenterology Volume: In press Issue: 11 Pages: 1073-1080
  • DOI: 10.1007/s00535-016-1189-x
  • Peer Reviewed / Open Access
• [Journal Article] A case of chronic inflammatory demyelinating polyradiculoneuropathy after treatment with pegylated interferon α-2a in a patient with chronic hepatitis B virus infection (2016)
  • Author(s): Naito H., Takeda I., Segawa A., Tsuge M., Maruyama H. and Matsumoto M.
  • Journal Title: Rinsho Shinkeigaku Volume: 56 Issue: 10 Pages: 672-677
  • DOI: 10.5692/clinicalneurol.cn-000888
  • NAID: 130005250055
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] de novo B型肝炎のインパクト (2016)
  • Author(s): 柘植雅貴、茶山一彰
  • Journal Title: 医学のあゆみ Volume: 258 Pages: 1144-1146
• [Journal Article] Improvement of renal dysfunction in a patient with HCV-related liver cirrhosis by daclatasvir and asunaprevir combination therapy: A case report. (2016)
  • Author(s): Tsuge M, Hiramatsu A, Shinohara F, Nakano N, Nakamura Y, Hatooka M, Morio K, Morio R, Kan H, Fujino H, Uchida T, Kobayashi T, Fukuhara T, Masaki K, Nakahara T, Ono A, Nagaoki Y, Miki D, Kawaoka T, Hiraga N, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 9 Pages: 944-948
  • DOI: 10.1111/hepr.12629
  • Peer Reviewed
• [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. (2016)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Journal of Gastroenterology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Factors associated with the effect of interferon-alpha sequential therapy in order to discontinue nucleoside/nucleotide analog treatment in patients with chronic hepatitis B. (2015)
  • Author(s): Matsumoto A., Yatsuhashi H., Nagaoka S., Suzuki Y., Hosaka T., Tsuge M., Chayama K., Kanda T., Yokosuka O., Nishiguchi S., Saito M., Miyase S., Kang J.H., Shinkai N., Tanaka Y., Umemura T. and Tanaka E.
  • Journal Title: Hepatology Research Volume: 45 Issue: 12 Pages: 1195-1202
  • DOI: 10.1111/hepr.12488
  • Peer Reviewed
• [Journal Article] Differences in serum microRNA profiles in hepatitis B and C virus infection. (2015)
  • Author(s): Akamatsu S, Hayes CN, Tsuge M, Miki D, Akiyama R, Abe H, Ochi H, Hiraga N, Imamura M, Takahashi S, Aikata H, Kawaoka T, Kawakami Y, Ohishi W, Chayama K.
  • Journal Title: J Infect. Volume: 70 Issue: 3 Pages: 273-287
  • DOI: 10.1016/j.jinf.2014.10.017
  • Peer Reviewed
• [Journal Article] Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice. (2015)
  • Author(s): Uchida T., Hiraga N., Imamura M., Tsuge M., Abe H., Hayes C.N., Aikata H., Ishida Y., Tateno C., Yoshizato K., Ohdan H., Murakami K. and Chayama K.
  • Journal Title: Journal of Virology Volume: 89 Issue: 19 Pages: 10087-96
  • DOI: 10.1128/jvi.01126-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human microRNA hsa-miR-1231 suppresses hepatitis B virus replication by targeting core mRNA. (2014)
  • Author(s): Kohno T, Tsuge M, Murakami E, Hiraga N, Abe H, Miki D, Imamura M, Ochi H, Hayes CN, Chayama K.
  • Journal Title: J Viral Hepat. Volume: 21 Issue: 4 Pages: 369-375
  • DOI: 10.3851/imp2777
  • Peer Reviewed
• [Presentation] 1.B型肝炎ウイルス（HBV）感染に伴う肝細胞内IL8発現亢進と細胞内インターフェロン反応性の検討 (2017)
  • Author(s): 柘植 雅貴、内田宅郎、茶山一彰
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 2.B型慢性肝疾患に対するエンテカビル治療と血清サイトカインの変化 (2017)
  • Author(s): 柘植 雅貴、栗原美緒、茶山一彰
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 3.核酸アナログ治療併用の有無によるインターフェロン治療効果の検討 (2017)
  • Author(s): 柘植雅貴、川上由育、茶山一彰
  • Organizer: 第21回日本肝臓学大会
• [Presentation] 4.Hepatitis B virus up-regulates IL8 expression via endoplasmic reticulum stress and leads to suppress interferon responsiveness. (2017)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Murakami E, Abe-Chayama H, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K
  • Organizer: AASLD（米国肝臓学会）2017
  • Int'l Joint Research
• [Presentation] 5.核酸アナログ治療例に対するペグインターフェロン治療とHBs低下に関する検討 (2017)
  • Author(s): 柘植雅貴、川上由育、内川慎介、児玉健一郎、西田祐乃、稲垣有希、盛生 慶、中原隆志、村上英介、河岡友和、平松 憲、今村道雄、相方 浩、川上広育、茶山一彰
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] B型肝炎ウイルス感染に伴うヒト肝細胞内遺伝子の発現変化の解析 (2016)
  • Author(s): 柘植 雅貴、平賀伸彦、茶山一彰
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉県幕張
• [Presentation] 核酸アナログ投与B型慢性肝炎症例に対するHBIG投与の有効性 (2016)
  • Author(s): 柘植 雅貴、川上由育、茶山一彰
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉県幕張
• [Presentation] HBV genotypeに伴う核酸アナログ感受性に関する検討 (2016)
  • Author(s): 柘植 雅貴、村上英介、茶山 一彰
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京都
• [Presentation] ヒト肝細胞キメラマウスを用いたB型肝炎ウイルス遺伝子型による感染肝細胞内遺伝子発現変化の検討 (2016)
  • Author(s): 柘植雅貴、内田宅郎、菅宏美、阿部弘美、三木大樹、河岡友和、平賀伸彦、今村道雄、相方浩、越智秀典、茶山一彰
  • Organizer: 第12回広島肝臓プロジェクト研究センターシンポジウム
  • Place of Presentation: 広島県広島市
• [Presentation] 核酸アナログ先行投与によるインターフェロン反応性の改善 (2016)
  • Author(s): 柘植雅貴、森奈美、長沖祐子、河岡友和、平松憲、今村道雄、川上由育、相方浩、辻恵二、川上広育、茶山一彰
  • Organizer: DDW2016
  • Place of Presentation: 兵庫県神戸市
• [Presentation] ヒト肝細胞キメラマウスを用いたB型肝炎ウイルス遺伝子型による感染肝細胞内遺伝子発現変化の検討 (2016)
  • Author(s): 柘植雅貴、平賀伸彦、内田宅郎、菅宏美、阿部弘美、三木大樹、河岡友和、今村道雄、相方浩、越智秀典、茶山一彰
  • Organizer: 臨床分子医学会2016
  • Place of Presentation: 東京都
• [Presentation] Evaluation of antiviral effects of a novel site-specific pegylated interferon beta using humanized mouse model (2016)
  • Author(s): Masataka Tsuge, Takuro Uchida, Hiromi Kan, Hiromi Abe, Daiki Miki, Michio Imamura, Hidenori Ochi, C Nelson Hayes, Reiko Shimozono, Tomokatsu Iwamura, Hideki Narumi, Tomohiko Suzuki, Mie Kainoh, Tadatsugu Taniguchi, Kazuaki Chayama
  • Organizer: AASLD2016
  • Place of Presentation: 米国、ボストン
  • Int'l Joint Research
• [Presentation] HBV RNA量を用いた核酸アナログ中止後再燃予測 (2015)
  • Author(s): 柘植雅貴、川上広育、茶山一彰
  • Organizer: 第42回日本肝臓学会西部会（パネルディスカッション）
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-25
• [Presentation] Difference of intracellular responses by HBV genotype A and C infection in humanized mouse model (2015)
  • Author(s): Masataka Tsuge, Nobuhiko Hiraga, Hiromi Abe, Daiki Miki, Michio Imamura, Hidenori Ochi, C Nelson Hayes, Kazuaki Chayama
  • Organizer: AASLD2016（ポスター）
  • Place of Presentation: 米国（サンフランシスコ）
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [Presentation] B型肝炎治療の現状 (2015)
  • Author(s): 柘植雅貴
  • Organizer: JDDW 2015（ランチョンセミナー）
  • Place of Presentation: 東京
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] HBV genotype C感染例におけるHBs抗原消失に関する検討 (2015)
  • Author(s): 柘植雅貴、村上英介、茶山一彰
  • Organizer: JDDW 2015（ワークショップ）
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] HBV genotypeと核酸アナログの抗ウイルス効果 (2015)
  • Author(s): 柘植 雅貴、村上英介、平賀 伸彦、阿部弘美、今村 道雄、秋田智之 、田中純子 、茶山 一彰
  • Organizer: 第11回広島肝臓プロジェクト研究センターシンポジウム（一般演題）
  • Place of Presentation: 広島
  • Year and Date: 2015-07-04
• [Presentation] HBV感染に伴うmicroRNA発現変化と miRNAによるHBV複製制御 (2015)
  • Author(s): 柘植雅貴、平賀伸彦、村上英介、阿部弘美、三木大樹、河岡友和、平松 憲、今村道雄、川上由育、相方 浩、越智秀典、茶山一彰
  • Organizer: 第51回日本肝臓学会総会（一般演題）
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-22
• [Presentation] 核酸アナログ中止例における HBVコア蛋白のアミノ酸変異に関する解析 (2015)
  • Author(s): 村上英介、柘植雅貴、内田宅郎、菅 宏美、柾木慶一、本田洋士、中原隆志、大野敦司、平賀伸彦、河岡友和、平松 憲、今村道雄、相方 浩、茶山一彰、川上広育
  • Organizer: 第51回日本肝臓学会総会（一般演題）
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-22
• [Presentation] 当院におけるHBVキャリアのHBs抗原陰性化と肝発癌に関する検討 (2015)
  • Author(s): 村上英介、柘植雅貴、茶山一彰
  • Organizer: 第101回日本消化病学会総会（シンポジウム）
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-16
• [Presentation] 核酸アナログ先行投与によるインターフェロン反応性の変化 (2015)
  • Author(s): 柘植雅貴、平賀伸彦、茶山一彰
  • Organizer: 第101回日本消化病学会総会（ワークショップ）
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-14
• [Patent(Industrial Property Rights)] 高力価のB型肝炎ウイルスを産生する細胞およびその作製方法 (2015)
  • Inventor(s): 柘植雅貴、茶山一彰
  • Industrial Property Rights Holder: 柘植雅貴、茶山一彰
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-04-10