Research on hepatic pathogenesis after achieving SVR by DAA treatment for hepatitis C

• Project/Area Number: 20K08369
• 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: National Institute of Infectious Diseases
• Principal Investigator: Wakita Takaji 国立感染症研究所, 所長, 所長 (40280789)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: C型肝炎ウイルス / HCV / SVR / 肝発癌 / DAA / Ｃ型肝炎ウイルス / 肝病態

Outline of Research at the Start

DAA投与により、多くのHCVキャリアでSVRが達成可能となった。ウイルス排除によるＣ型肝炎治療の目的は肝発癌の防止にあり、SVR達成後に発癌率は明らかに低下するが、一部ではSVR後の肝障害の持続や、肝発癌が問題となっている。長期間の持続感染による肝炎による細胞障害、組織障害の分子機構は十分に解明されておらず、これらの障害がDAA治療により正常化するのかは解明されていない。これまでに樹立したHCV感染モデル、動物モデル、臨床材料を用いて、HCV排除後の肝障害や発癌に関与する肝細胞の微細構造変化、遺伝子発現変化を網羅的に解析し、関連する宿主因子を同定し、肝障害改善に資する基盤的研究をおこなう。

Outline of Final Research Achievements

HCV persistently infects hepatocytes and causes chronic liver damage. As fibrosis progresses, liver lobules are remodeled, and the hemodynamics of the liver also change. Therefore, liver damage caused by persistent HCV infection involves not only viral infection and host immune response, but also changes due to tissue remodeling of the liver. Therefore, even after achieving SVR, liver injury may continue and lead to hepatocarcinogenesis. In this study, we focused on the organelle structure and gene expression changes of infected cells. We constructed HCV-uninfected cells, infected cells, and post-infection-excluded cells on a culture cell basis, and observed HCV elimination from HCV infection. There were genes that changed reversibly and irreversibly in these cells. We will further analyze these cells, analyze human liver chimeric mice and patient specimens, clarify genes that are reversibly and irreversibly changed in common, and clarify host markers related to liver damage.

Academic Significance and Societal Importance of the Research Achievements

HCVは抗ウイルス療法により95%以上のウイルス排除率が達成されている。しかし、DAAによるSVR達成後に一部の症例ではウイルス排除後の肝障害の持続や、肝発癌が問題となっている。本研究ではウイルス感染およびウイルス排除に伴う肝細胞および肝組織変化に着目し、ウイルス感染による肝臓の可逆的および不可逆的変化を解析する。ウイルス排除後も回復しない不可逆的変化とその原因となる宿主因子について解明できれば、SVR達成後の肝障害および肝発がん予防に資する検査法および治療法開発につながることが期待される。

Research Products

• [Journal Article] Patient-derived monoclonal antibody neutralizes HCV infection in vitro and vivo without generating escape mutants (2022)
  • Author(s): Yokokawa Hiroshi、Shinohara Midori、Teraoka Yuji、Imamura Michio、Nakamura Noriko、Watanabe Noriyuki、Date Tomoko、Aizaki Hideki、Iwamura Tomokatsu、Narumi Hideki、Chayama Kazuaki、Wakita Takaji
  • Journal Title: PLOS ONE Volume: 17 Issue: 9 Pages: e0274283-e0274283
  • DOI: 10.1371/journal.pone.0274283
  • Peer Reviewed / Open Access
• [Journal Article] A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection (2022)
  • Author(s): Shirasago Yoshitaka、Fukazawa Hidesuke、Nagase Shotaro、Shimizu Yoshimi、Mizukami Tomoharu、Wakita Takaji、Suzuki Tetsuro、Tani Hideki、Kondoh Masuo、Kuroda Takuya、Yasuda Satoshi、Sato Yoji、Hanada Kentaro、Fukasawa Masayoshi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 20243-20243
  • DOI: 10.1038/s41598-022-23824-3
  • Peer Reviewed / Open Access
• [Journal Article] Independent evolution of multi-dominant viral genome species observed in a hepatitis C virus carrier (2022)
  • Author(s): Ando Tomomi、Aizaki Hideki、Sugiyama Masaya、Date Tomoko、Hayashi Kazuhiko、Ishigami Masatoshi、Katano Yoshiaki、Goto Hidemi、Mizokami Masashi、Muramatsu Masamichi、Kuroda Makoto、Wakita Takaji
  • Journal Title: Biochemistry and Biophysics Reports Volume: 32 Pages: 101327-101327
  • DOI: 10.1016/j.bbrep.2022.101327
  • Peer Reviewed
• [Journal Article] Development and Use of a Kinetical and Real-Time Monitoring System to Analyze the Replication of Hepatitis C Virus (2022)
  • Author(s): Xiaoyu Li, Masahiko Ito, Haruyo Aoyagi, Asako Murayama, Hideki Aizaki, Masayoshi Fukasawa, Takanobu Kato, Takaji Wakita, Tetsuro Suzuki
  • Journal Title: Int J Mol Sci Volume: 23 Issue: 15 Pages: 8711-8711
  • DOI: 10.3390/ijms23158711
  • Peer Reviewed / Open Access
• [Journal Article] Hepatitis C Virus-Induced ROS/JNK Signaling Pathway Activates the E3 Ubiquitin Ligase Itch to Promote the Release of HCV Particles via Polyubiquitylation of VPS4A (2022)
  • Author(s): Deng Lin、Liang Yujiao、Ariffianto Adi、Matsui Chieko、Abe Takayuki、Muramatsu Masamichi、Wakita Takaji、Maki Masatoshi、Shibata Hideki、Shoji Ikuo
  • Journal Title: Journal of Virology Volume: 96 Issue: 6 Pages: 1811-21
  • DOI: 10.1128/jvi.01811-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of an intervention system for linkage-to-care and follow-up for hepatitis B and C virus carriers (2021)
  • Author(s): Kikuchi Minami、Sawabe Motoji、Aoyagi Haruyo、Wakae Kosho、Watashi Koichi、Hattori Satoru、Kawabe Naoto、Yoshioka Kentaro、Tanaka Junko、Muramatsu Masamichi、Wakita Takaji、Aizaki Hideki
  • Journal Title: Hepatology International Volume: 16 Issue: 1 Pages: 68-80
  • DOI: 10.1007/s12072-021-10269-5
  • Peer Reviewed
• [Journal Article] Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus (2021)
  • Author(s): Zheng Xin、Guo Rui、Liu Qingbo、Wakae Kousho、Watanabe Noriyuki、Fukano Kento、Que Lusheng、Li Yingfang、Aly Hussein H.、Watashi Koichi、Suzuki Ryosuke、Murayama Asako、Kato Takanobu、Aizaki Hideki、Wakita Takaji、Huang Xiaoxiao、Yan Yi、Song Shao-Jiang、Muramatsu Masamichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 567 Pages: 1-8
  • DOI: 10.1016/j.bbrc.2021.06.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus (2021)
  • Author(s): Takeda Haruhiko、Takai Atsushi、Iguchi Eriko、Mishima Masako、Arasawa Soichi、Kumagai Ken、Eso Yuji、Shimizu Takahiro、Takahashi Ken、Ueda Yoshihide、Taura Kojiro、Hatano Etsuro、Iijima Hiroko、Aoyagi Haruyo、Aizaki Hideki、Marusawa Hiroyuki、Wakita Takaji、Seno Hiroshi
  • Journal Title: Carcinogenesis Volume: 42 Issue: 5 Pages: 672-684
  • DOI: 10.1093/carcin/bgab014
  • Peer Reviewed
• [Journal Article] Required concentration index quantifies effective drug combinations against hepatitis C virus infection (2021)
  • Author(s): Kakizoe Yusuke、Koizumi Yoshiki、Ikoma Yukino、Ohashi Hirofumi、Wakita Takaji、Iwami Shingo、Watashi Koichi
  • Journal Title: Theoretical Biology and Medical Modelling Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12976-020-00135-6
  • Peer Reviewed / Open Access
• [Journal Article] Identification of microRNA associated with the elimination of hepatitis C virus genotype 1b by direct‐acting antiviral therapies (2021)
  • Author(s): Yoneyama H, Morishita A, Iwama H, Fujita K, Takahiro Masaki, Tani J, Tadokoro T, Nomura T, Sakamoto T, Oura K, Takuma K, Nakahara M, Mimura S, Deguchi A, Oryu M, Tsutsui K, Himoto T, Shimotohno K, Wakita T, Kobara H, Masaki T
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 36 Issue: 4 Pages: 1126-1135
  • DOI: 10.1111/jgh.15224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Occludin‐binding single‐chain variable fragment and antigen‐binding fragment antibodies prevent hepatitis C virus infection (2020)
  • Author(s): Shimizu Yoshimi、Shinoda Takehiro、Shirasago Yoshitaka、Kondoh Masuo、Shinya Naoko、Hanada Kentaro、Yagi Kiyohito、Suzuki Tetsuro、Wakita Takaji、Kimura‐Someya Tomomi、Shirouzu Mikako、Fukasawa Masayoshi
  • Journal Title: FEBS Letters Volume: 595 Issue: 2 Pages: 220-229
  • DOI: 10.1002/1873-3468.13975
  • Peer Reviewed / Open Access
• [Journal Article] Sphingomyelin Is Essential for the Structure and Function of the Double-Membrane Vesicles in Hepatitis C Virus RNA Replication Factories (2020)
  • Author(s): Gewaid H, Aoyagi H, Arita M, Watashi K, Suzuki R, Sakai S, Kumagai K, Yamaji T, Fukasawa M, Kato F, Hishiki T, Mimata A, Sakamaki Y, Ichinose S, Hanada K, Muramatsu M, Wakita T, Aizaki H.
  • Journal Title: J Virol Volume: 94 Issue: 23
  • DOI: 10.1128/jvi.01080-20
  • Peer Reviewed
• [Journal Article] Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma (2020)
  • Author(s): S. Iwanami, K. Kitagawa, H. Ohashi, Y. Asai, K. Shionoya, W. Saso, K. Nishioka, H. Inaba, S. Nakaoka, T. Wakita, O. Diekmann, S. Iwami and K. Watashi
  • Journal Title: PLoS Biology Volume: 18(7) Issue: 7 Pages: 3000562-3000562
  • DOI: 10.1371/journal.pbio.3000562
  • NAID: 120006872724
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevalence of equine hepacivirus infection in Mongolia (2020)
  • Author(s): Date Tomoko、Sugiyama Masaya、Lkhagvasuren Damdindorj、Wakita Takaji、Oyunsuren Tsendsuren、Mizokami Masashi
  • Journal Title: Virus Research Volume: 282 Pages: 197940-197940
  • DOI: 10.1016/j.virusres.2020.197940
  • Peer Reviewed
• [Presentation] RHV RNA複製の高いcured細胞の樹立とその評価 (2022)
  • Author(s): 園部円、渡邉則幸、鈴木貴也、小柳円、有村裕、相崎英樹、村松正道、脇田隆字
  • Organizer: 第69回日本ウイルス学会学術集会
• [Presentation] ラット肝炎ウイルス感染動物モデルを用いたC型肝炎ウイルスワクチン開発 (2022)
  • Author(s): 渡邉則幸、園部円、鈴木貴也、李天成、須崎百合子、網康至、花木賢一、小柳円、有村裕、鈴木亮介、相崎英樹、村松正道、脇田隆字
  • Organizer: 第69回日本ウイルス学会学術集会
• [Presentation] ウイルス肝炎基礎研究の新たな展開 (2022)
  • Author(s): 脇田隆字、相崎英樹
  • Organizer: 日本消化器病学会総会
  • Invited
• [Presentation] 30 years of HCV Virology (2021)
  • Author(s): Takaji Wakita
  • Organizer: 27th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research / Invited
• [Presentation] HCV virology and HCC after SVR (2021)
  • Author(s): Takaji Wakita, Haruyo Aoyagi, Tomoko Date, Noriyuki Watanabe, Hideki Aizaki, Masamichi Muramats
  • Organizer: The 17th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD)
  • Int'l Joint Research / Invited
• [Presentation] Hepatocellular carcinoma in SVR achieved CHC patients after DAA treatment (2021)
  • Author(s): Takaji Wakita, Haruyo Aoyagi, Tomoko Date, Noriyuki Watanabe, Hideki Aizaki, Masamichi Muramatsu
  • Organizer: JSH International Liver Conference 2021
  • Int'l Joint Research / Invited
• [Presentation] 今年のノーベル医学生理学賞は「The discovery of Hepatitis C Virus（Ｃ型肝炎ウイルスの発見）」が受賞したことを祝して (2021)
  • Author(s): 脇田隆字
  • Organizer: 第43回日本肝臓学会東部会
  • Invited
• [Presentation] 今年のノーベル医学生理学賞は「The discovery of Hepatitis C Virus (Ｃ型肝炎ウイルスの発見)」が受賞したことを祝して (2020)
  • Author(s): 脇田隆字
  • Organizer: 第43回日本肝臓学会東部会
  • Invited