Analyses of antiviral mechanisms by interferon treatment on hepatitis B virus replication

• Project/Area Number: 18K07973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: B型肝炎 / インターフェロン / 抗ウイルス効果 / ヒト肝細胞キメラマウス / B型肝炎ウイルス / 遺伝子発現解析 / cccDNA

Outline of Final Research Achievements

I compared the induction of interferon stimulated genes (ISGs) between by PEG-IFNα2a and PEG-IFNβ using hepatoma cell line. When I treated hepatoma cells with PEG-IFNs, I found that 34% of ISGs were more strongly induced by PEG-IFNβ treatment rather than by PEG-IFNα2a treatment. Additionally, I also found that the induction rates of several ISGs were enhanced or reduced by HBV expression.
To identify the molecular target for the improvement of antiviral effects by interferon treatment, I focused on gene A and further analyses were performed. I found that gene A is upregulated by HBV infection using human hepatocyte chimeric mouse model and also found that the expression of gene A could be regulated by HBx protein using in vitro HBV expression model. Furthermore, I clarified that host immune response might be suppressed by gene A upregulation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果から、同定した遺伝子は、B型肝炎ウイルス感染に伴い活性化する生体内の免疫応答やインターフェロンにより活性化された免疫応答を回避し、B型肝炎ウイルスの持続感染に関与しているものと考えられる。現在、同遺伝子の発現制御を行い、インターフェロンによる抗ウイルス効果を制御できる化合物を探索中であり、化合物を同定できれば、B型肝炎ウイルス持続感染者に対する抗ウイルス療法の新たなオプションとなりうると考えられる。

Research Products

• [Int'l Joint Research] Loyola University Chicago/Virginia Tech(米国)
• [Int'l Joint Research] Ｌｏｙｏｌａ Ｕｎｉｖｅｒｓｉｔｙ Ｃｈｉｃａｇｏ ｍｅｄｉｃａｌ ｃｅｎｔｅｒ(米国)
• [Int'l Joint Research] Loyola University Chicago Medical Center(米国)
• [Journal Article] Signal Activation of Hepatitis B Virus-Related Hepatocarcinogenesis by Up-regulation of SUV39h1 (2020)
  • Author(s): Takeuchi Yasue、Tsuge Masataka、Tsushima Ken、Suehiro Yosuke、Fujino Hatsue、Ono Atsushi、Yamauchi Masami、Makokha Grace Naswa、Nakahara Takashi、Murakami Eisuke、Abe-Chayama Hiromi、Kawaoka Tomokazu、Miki Daiki、Imamura Michio、Aikata Hiroshi、Hayes C Nelson、Tateno Chise、Chayama Kazuaki
  • Journal Title: The Journal of Infectious Diseases Volume: 222 Issue: 12 Pages: 2061-2070
  • DOI: 10.1093/infdis/jiaa317
  • Peer Reviewed
• [Journal Article] Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B (2020)
  • Author(s): Matsumoto A, Nishiguchi S, Enomoto H, Tanaka Y, Shinkai N, Okuse C, Kang JH, Matsui T, Miyase S, Yatsuhashi H, Nagaoka S, Kanda T, Enomoto M, Yamada R, Hiramatsu N, Saito S, Takaguchi K, Ito K, Masaki T, Morihara D, Tsuge M, Chayama K, Ikeda F, Kagawa T, Kondo Y, Murata K, Tanaka E.
  • Journal Title: J Gastroenterol. Volume: 55(10) Issue: 10 Pages: 977-989
  • DOI: 10.1007/s00535-020-01707-6
  • Peer Reviewed
• [Journal Article] Abatacept treatment for patients with severe acute hepatitis caused by hepatitis B virus infection-Pilot study (2020)
  • Author(s): Teraoka Yuji、Imamura Michio、Uchida Takuro、Ohya Kazuki、Morio Kei、Fujino Hatsue、Ono Atsushi、Nakahara Takashi、Murakami Eisuke、Yamauchi Masami、Kawaoka Tomokazu、Miki Daiki、Tsuge Masataka、Hiramatsu Akira、Abe‐Chayama Hiromi、Nelson Hayes C.、Aikata Hiroshi、Chayama Kazuaki
  • Journal Title: Journal of Viral Hepatitis Volume: 28 Issue: 2 Pages: 400-409
  • DOI: 10.1111/jvh.13441
  • Peer Reviewed
• [Journal Article] Regulation of the Hepatitis B virus replication and gene expression by the multi-functional protein TARDBP (2019)
  • Author(s): Makokha Grace Naswa、Abe-Chayama Hiromi、Chowdhury Sajeda、Hayes C. Nelson、Tsuge Masataka、Yoshima Tadahiko、Ishida Yuji、Zhang Yizhou、Uchida Takuro、Tateno Chise、Akiyama Rie、Chayama Kazuaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 8462-8462
  • DOI: 10.1038/s41598-019-44934-5
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice (2019)
  • Author(s): Tsushima K, Tsuge M, Hiraga N, Uchida T, Murakami E, Makokha GN, Kurihara M, Nomura Motonobu, Hiyama Y, Fujino H, Ono A, Nakahara T, Yamauchi M, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Aikata H, Hayes CN, Chayama K
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 7 Pages: 650-659
  • DOI: 10.1007/s00535-019-01558-w
  • Peer Reviewed / Open Access
• [Journal Article] ヒト肝細胞キメラマウスを用いたB型肝炎研究の最前線 (2019)
  • Author(s): 柘植雅貴、茶山一彰
  • Journal Title: 消化器・肝臓内科 Volume: 6 Pages: 271-278
• [Journal Article] Early Multiphasic HBV Infection Initiation Kinetics Is Not Clone-Specific and Is Not Affected by Hepatitis D Virus (HDV) Infection (2019)
  • Author(s): Tsuge Masataka, Uchida Takuro, Walsh Kevin, Ishida Yuji, Tateno Chise, Kumar Upendra, Glenn Jeffrey, Koh Christopher, Heller Theo, Uprichard Susan, Dahari Harel, Chayama Kazuaki
  • Journal Title: Viruses Volume: 11 Issue: 3 Pages: 263-263
  • DOI: 10.3390/v11030263
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CTL-associated and NK cell-associated immune responses induce different HBV DNA reduction patterns in chronic hepatitis B patients (2018)
  • Author(s): Nomura M, Tsuge M, Uchida To, Hiraga N, Kurihara M, Tsushima K, Fujino H, Nakahara T, Murakami E, Abe-Chayama H, Kawaoka T, Miki D, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Ochi H, Zhang Y, Makokha GN, Hayes CN, Tanaka S, Chayama K
  • Journal Title: Journal of Viral Hepatitis Volume: 25 Issue: 12 Pages: 1555-1564
  • DOI: 10.1111/jvh.12970
  • Peer Reviewed
• [Journal Article] Reduction of hepatitis B surface antigen in sequential versus add-on pegylated interferon to nucleoside/nucleotide analogue therapy in HBe-antigen-negative chronic hepatitis B patients: a pilot study (2018)
  • Author(s): Tatsukawa Yumiko, Tsuge Masataka, Kawakami Yoshiiku, Murakami Eisuke, Kurihara Mio, Nomura Motonobu, Tsushima Ken, Uchida Takuro, Nakahara Takashi, Miki Daiki, Kawaoka Tomokazu, Abe-Chayama Hiromi, Imamura Michio, Aikata Hiroshi, Ochi Hidenori, Hayes C Nelson, Kawakami Hiroiku, Chayama Kazuaki
  • Journal Title: Antiviral Therapy Volume: 23 Issue: 8 Pages: 639-646
  • DOI: 10.3851/imp3240
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes (2018)
  • Author(s): Tsuge M, Hiraga N, Zhang Y, Yamashita M, Sato O, Oka N, Shiraishi K, Izaki Y, Makokha GN, Uchida T, Kurihara M, Nomura M, Tsushima K, Nakahara T, Murakami E, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Fujita T, Chayama K
  • Journal Title: Virology Volume: 525 Pages: 48-61
  • DOI: 10.1016/j.virol.2018.08.020
  • Peer Reviewed
• [Presentation] HBs抗原陰性化を目指したB型肝炎治療 ～実臨床成績、基礎研究の現状～ (2020)
  • Author(s): 柘植雅貴
  • Organizer: JDDW2020 ブレックファーストセミナー19
  • Invited
• [Presentation] 核酸アナログ投与B型慢性肝炎症例に対するHBIG治療成績と奏効に寄与する因子の検討 (2020)
  • Author(s): 柘植 雅貴、三木大樹、茶山一彰
  • Organizer: 第56回日本肝臓学会総会 パネルディスカッション2
• [Presentation] 新規PEG-IFNβ製剤を用いた抗HBV効果の検討と抗ウイルス効果向上の試み (2020)
  • Author(s): 竹内泰江，柘植雅貴，茶山一彰
  • Organizer: 第56回日本肝臓学会総会 シンポジウム5
• [Presentation] エンテカビル治療中のHBV関連マーカーの変化に及ぼす血清サイトカインの影響 (2020)
  • Author(s): 竹内泰江，柘植雅貴，茶山一彰
  • Organizer: 第106回日本消化器病学会総会 シンポジウム6
• [Presentation] IL8の発現制御によるHBVに対するIFN治療改善の可能性 (2020)
  • Author(s): 柘植 雅貴、津島 健、茶山 一彰
  • Organizer: 第106回日本消化器病学会総会 パネルディスカッション5
• [Presentation] CTL-associated and NK cell-associated immune responses induce different HBV DNA reduction patterns in chronic HBV infection. (2019)
  • Author(s): Masataka Tsuge, Motonobu Nomura, Takuro Uchida, Hiromi Abe-Chayama, Daiki Miki, Michio Imamura, Hiroshi Aikata, Grace Naswa Makokha, C. Nelson Hayes, Kazuaki Chayama
  • Organizer: 7th Japan-Taiwan-Korea HBV Research Symposium
  • Int'l Joint Research
• [Presentation] 2.核酸アナログ・ペグインターフェロン併用療法におけるHBs低下に寄与する因子の検討 (2019)
  • Author(s): 柘植雅貴、辰川裕美子、茶山一彰
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] 症例から学ぶ B型肝炎の診断・治療の最前線 (2019)
  • Author(s): 柘植雅貴
  • Organizer: 第55回日本肝臓学会総会
  • Invited
• [Presentation] Investigation of infectivity of serum-derived HBV from patients and human hepatocyte chimeric mouse to HepG2/NTCP cells. (2019)
  • Author(s): Hatsue Fujino, Miko Namba, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Masami Yamauchi, Tomokazu Kawaoka, Daiki Miki, Masataka Tsuge, Hiromi Abe-Chayama, C. Hayes Nelson, Michio Imamura, Hiroshi Aikata, Kazuaki Chayama
  • Organizer: International HBV meeting 2019
  • Int'l Joint Research
• [Presentation] Analysis of the association between HBV infection and long-term trends in intrahepatic gene expression. (2019)
  • Author(s): Masataka Tsuge, Ken Tsushima, Nobuhiko Hiraga, Takuro Uchida, Michio Imamura, C. Hayes Nelson, Harel Dahari, Susan L. Uprichard, Kazuaki Chayama
  • Organizer: International HBV meeting 2019
  • Int'l Joint Research
• [Presentation] Serum atutotaxin levels is useful to evaluate fibrosis during entecavir therapy and to predict the development of hepatocellular carcinoma in patients with chronic hepatitis B. (2019)
  • Author(s): Hatsue Fujino, Kei Morio, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Masami Yamauchi, Tomokazu Kawaoka, Daiki Miki, Masataka Tsuge, Hiromi Abe-Chayama, C. Hayes Nelson, Michio Imamura, Hiroshi Aikata, Kazuaki Chayama
  • Organizer: International HBV meeting 2019
  • Int'l Joint Research
• [Presentation] 核酸アナログ・ペグインターフェロン併用療法におけるHBs低下に寄与する因子の検討 (2019)
  • Author(s): 藤野初江、柘植雅貴、寺岡雄吏、盛生慶、大野敦司、中原隆志、村上英介、河岡友和、三木大樹、平松憲、今村道雄、相方浩、茶山一彰
  • Organizer: 第43回日本肝臓学会西部会
• [Presentation] The influence of histone methyltransferase SUV39h1 on hepatitis B virus related hepatocarcinogenesis (2018)
  • Author(s): Ken Tsushima, Masataka Tsuge, Takuro Uchida, Michio Imamura, Mitsutaka Osawa, Hiromi Abe-Chayama, Grace Naswa Makokha, Hiroshi Aikata, Kazuaki Chayama
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] B型肝炎治療の現状と新規治療薬開発の動向 (2018)
  • Author(s): 柘植雅貴
  • Organizer: 広島肝炎ウイルスセミナー
  • Invited
• [Presentation] 脂質代謝と肝炎ウイルス増殖との関連 (2018)
  • Author(s): 柘植雅貴
  • Organizer: Up To Date Seminar for Researchers
  • Invited
• [Presentation] 核酸アナログ治療後のペグインターフェロン治療におけるHBs低下に寄与する因子の検討 (2018)
  • Author(s): 柘植雅貴、辰川裕美子、茶山一彰
  • Organizer: JDDW2018
• [Presentation] 新規ペグ化インターフェロンβによるB型肝炎ウイルスに対する抗ウイルス効果の検討 (2018)
  • Author(s): 柘植 雅貴、内田宅郎、茶山一彰
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] B型肝炎ウイルス（HBV）関連肝疾患に対する肝移植とHBV再感染の解析 (2018)
  • Author(s): 柘植 雅貴、今村 道雄、茶山一彰
  • Organizer: 第104回日本消化器学会総会