Analysis of mechanism of HCV particle formation, secretion, and associated cellular factor

• Project/Area Number: 26461021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: Morikawa Kenichi 北海道大学, 大学病院, 助教 (60384377)
• Research Collaborator: WAKITA TAKAJI 国立感染症研究所, 副所長 (40280789) ; DATE TOMOKO 国立感染症研究所, ウイルス第二部, 研究員 (40392360) ; SHIMAZAKI TOMOE 北海道大学, 医学(系)研究科(研究院), 学術研究員 (40721494)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: C型肝炎ウイルス / GPｘ８ / ウイルス粒子形成 / ウイルス粒子分泌 / 細胞性因子 / GPx8 / 粒子形成 / ウイルス分泌 / NS3-4Aプロテアーゼ / HCVNS3-4Aプロテアーゼ

Outline of Final Research Achievements

We identified that Glutachione peroxidase 8 (GPx8), a membrane-associated peroxidase involved in disulfide bond formation in the endoplasmic reticulum, as a novel cellular substrate of the HCV NS3-4A protease. The aim of this study was to analyze the association between GPx8 and HCV life cycle, especially focused on HCV particle formation and assembly. The functional studies of GPx8 on HCV life cycle, involving overexpression and RNA silencing, revealed that GPx8 is a proviral factor involved in viral particle production but not in HCV entry or RNA replication. GPx8 is a proviral host factor cleaved by the HCV NS3-4A protease. Studies investigating the consequences of cleavage for GPx8 function are underway. The identification of novel cellular substrates of the HCV NS3-4A protease should yield new insights into the HCV life cycle and the pathogenesis of hepatitis C and may reveal novel angles for therapeutic intervention.

Research Products

• [Journal Article] Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy (2017)
  • Author(s): Suda G, Ogawa K, Yamamoto Y, Katagiri M, Furuya K, Kumagai K, Konno J, Kimura M, Kawagishi N, Ohara M, Umemura M, Ito J, Izumi T, Nakai M, Sho T, Natsuizaka M, Morikawa K, Tsubota A, Shimada N, Iio E, Tanaka Y, Sakamoto N; NORTE Study Group.
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 10 Pages: 1122-1129
  • DOI: 10.1007/s00535-017-1328-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatitis B virus X protein impairs α-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A. (2017)
  • Author(s): Tsunematsu S, Suda G, Yamasaki K, Kimura M, Izumi T, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Tanaka Y, Watashi K, Wakita T, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 2 Pages: 267-275
  • DOI: 10.1002/jmv.24643
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus infected patients with renal impairment (2017)
  • Author(s): Suda G, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Kudo M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N; NORTE Study Group.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1127-1136
  • DOI: 10.1111/hepr.12851
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination of neutrophil-to-lymphocyte ratio and early des-gamma-carboxyprothrombin change ratio as a useful predictor of treatment response for hepatic arterial infusion chemotherapy against advanced hepatocellular carcinoma (2017)
  • Author(s): Tsunematsu S, Suda G, Yamasaki K, Kimura M, Izumi T, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Kamiyama T, Taketomi A, Sakamoto N.
  • Journal Title: Hepatol Res Volume: 47(6) Issue: 6 Pages: 533-541
  • DOI: 10.1111/hepr.12775
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel Treatment of Hepatitis C Virus Infection for Patients with Renal Impairment (2016)
  • Author(s): Suda G, Ogawa K, Kimura M, Nakai M, Sho T, Morikawa K, Sakamoto N.
  • Journal Title: J Clin Transl Hepatol Volume: 4(4) Pages: 320-327
  • DOI: 10.14218/jcth.2016.00032
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection (2016)
  • Author(s): Morikawa K, Shimazaki T, Takeda R, Izumi T, Umumura M, Sakamoto N.
  • Journal Title: Ann Transl Med Volume: 4(18) Pages: 337-337
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection. (2016)
  • Author(s): Tsukuda Y, Suda G, Tsunematsu S, Ito J, Sato F, Terashita K, Nakai M, Sho T, Maehara O, Shimazaki T, Kimura M, Morikawa K, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 5 Pages: 857-866
  • DOI: 10.1002/jmv.24692
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection (2016)
  • Author(s): Ito J, Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kumagai K, Kikuchi H, Miyagishima T, Kobayashi T, Kimura M, Yamasaki K, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Terashita K, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto
  • Journal Title: Hepatol Res Volume: in press Issue: 13 Pages: 1294-1303
  • DOI: 10.1111/hepr.12685
  • Peer Reviewed / Open Access
• [Journal Article] Viral life cycle of hepatitis B virus : host factors and druggable targets. (2016)
  • Author(s): Morikawa K, Suda G, Sakamoto N
  • Journal Title: Hepatol Res Volume: EPub Issue: 9 Pages: 871-877
  • DOI: 10.1111/hepr.12650
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. (2016)
  • Author(s): Suda G, Kudo M, Nagasaka A, Furuya K, Yamamoto Y, Kobayashi T, Shinada K, Tateyama M, Konno J, Tsukuda Y, Yamasaki K, Kimura M, Umemura M, Izumi T, Tsunematsu S, Sato F, Terashita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N
  • Journal Title: J Gastroenterol Hepatol Volume: EPub Issue: 7 Pages: 733-740
  • DOI: 10.1007/s00535-016-1162-8
  • NAID: 120006313426
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 悪性リンパ腫肝浸潤により急性肝障害を呈した2例. (2016)
  • Author(s): 大森里紗、森川賢一､田代知映、三井祐太、藤原 峻、服部憲路、齋藤文護、塩沢英輔、吉田 仁.
  • Journal Title: 肝臓 Volume: 57(3) Pages: 125-131
  • NAID: 130005144108
  • Peer Reviewed
• [Journal Article] A pivotal role of Krüppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma. (2015)
  • Author(s): Maehara O, Sato F, Natsuizaka M, Asano A, Kubota Y, Itoh J, Tsunematsu S, Terashita K, Tsukuda Y, Nakai M, Sho T, Suda G, Morikawa K, Ogawa K, Chuma M, Nakagawa K, Ohnishi S, Komatsu Y, Whelan KA, Nakagawa H, Takeda H, Sakamoto N.
  • Journal Title: Cancer Biol Ther Volume: 16 Issue: 10 Pages: 14531461-14531461
  • DOI: 10.1080/15384047.2015.1070992
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased expression of immuno-inhibitory molecules on peripheral blood lymphocytes may suppress disease progression in autoimmune hepatitis. (2015)
  • Author(s): Hiraide-Sasagawa A, Hiroishi K, Shimazaki T, Eguchi J, Ishii S, Morikawa K, Sakaki M, Doi H, Omori R, Kajiwara A, Hayashi E, Shiina M, Hirayama Y, Imawari M.
  • Journal Title: Hepatology Research Volume: 45(11) Issue: 11 Pages: 1152-1154
  • DOI: 10.1111/hepr.12479
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma (2015)
  • Author(s): Tsunematsu S, Chuma M, Kamiyama T, Miyamoto N, Yabusaki S, Hatanaka K, Mitsuhashi T, Kamachi H, Yokoo H, Kakisaka T, Tsuruga Y, Orimo T, Wakayama K, Ito J, Sato F, Terashita K, Nakai M, Tsukuda Y, Sho T, Suda G, Morikawa K, Natsuizaka M, Nakanishi M, Ogawa K, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: Abdom Imaging Volume: 40 Issue: 6 Pages: 1492-9
  • DOI: 10.1007/s00261-015-0352-9
  • Peer Reviewed
• [Journal Article] Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β-induction by efficient MAVS cleavage. (2014)
  • Author(s): Welsch C, Haselow K, Gouttenoire J, Schneider M, Morikawa K, Martinez Y, Susser S, Sarrazin C, Zeuzem S, Antes I, Moradpour D, Lange CM.
  • Journal Title: Journal of Hepatology Volume: 62(4) Issue: 4 Pages: 779-784
  • DOI: 10.1016/j.jhep.2014.11.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vitamin D Receptor and Jak-STAT Signaling Crosstalk Results in Calcitriol-Mediated Increase of Hepatocellular Response to IFN-α. (2014)
  • Author(s): Lange CM, Gouttenoire J, Duong FH, Morikawa K, Heim MH, Moradpour D.
  • Journal Title: Journal of Immunology Volume: 192(12) Issue: 12 Pages: 6037-6044
  • DOI: 10.4049/jimmunol.1302296
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantitative proteomics identifies the membrane-associated peroxidase GPx8 as a cellular substrate of the hepatitis C virus NS3-4A protease. (2014)
  • Author(s): Morikawa K, Gouttenoire J, Hernandez C, Dao Thi VL, Tran HT, Lange CM, Dill MT, Heim MH, Donzé O, Penin F, Quadroni M, Moradpour D.
  • Journal Title: Hepatology Volume: 59(2) Issue: 2 Pages: 423-433
  • DOI: 10.1002/hep.26671
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Analysis of cellular factors involved in the particle formation and secretion of hepatitis C virus. (2016)
  • Author(s): Morikawa K, Suda G, Gouttenoire J, Moradpour D, Sakamoto N.
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Analysis of cellular factors involved in the particle formation and secretion of hepatitis C virus. (2016)
  • Author(s): Morikawa K, Izumi T, Umemura M, Ito J, Tsunematsu S, Sato F, Nakai M, Sho T, Suda G, Ogawa K, Sakamoto N.
  • Organizer: The 25th Asian Pacific Association for the Study of the Liver (APASL 2016).
  • Place of Presentation: 国際会議場パミール（東京都・港区）
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] Analysis of cellular factors involved in the particle formation and secretion of hepatitis C virus (2015)
  • Author(s): Kenichi Morikawa
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2015-11-23
• [Presentation] C型肝炎ウイルスの粒子形成・分泌機構の解明と関与する細胞性因子の解析. (2015)
  • Author(s): 森川賢一, 島崎とも江, 伊藤 淳, 常松聖司, 佐藤史幸, 寺下勝巳, 佃 曜子, 中井正人, 荘 拓也, 須田剛生, 夏井坂光輝, 小川浩司, 坂本直哉.
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2015-05-21
• [Presentation] 当院におけるGenotype 1b高ウイルス量C型慢性肝炎に対するLedipasvir/Sofosbuvir±Rivavirin併用療法の治療成績. (2015)
  • Author(s): 須田剛生, 小川浩司, 伊藤 淳, 佐藤史幸, 常松聖司, 佃 曜子, 寺下勝巳, 中井正人, 荘 拓也, 森川賢一, 夏井坂光輝, 坂本直哉.
  • Organizer: 第116回日本消化器病学会北海道支部例会.
  • 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: 2015-03-07
• [Presentation] Genotype 2型C型慢性肝炎に対するSofosbuvir/Rivavirin併用療法の治療成績. (2015)
  • Author(s): 小川浩司, 伊藤 淳, 常松聖司, 佐藤史幸, 寺下勝巳, 佃 曜子, 中井正人, 荘 拓也, 須田剛生, 森川賢一, 夏井坂光輝, 坂本直哉.
  • Organizer: 第116回日本消化器病学会北海道支部例会.
  • 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: 2015-03-07
• [Presentation] 肝移植後のC型慢性肝炎に対しシメプレビルを含む3剤併用療法を施行した4症例. (2015)
  • Author(s): 伊藤 淳, 常松聖司, 佐藤史幸, 佃 曜子, 寺下勝巳, 中井正人, 荘 拓也, 須田剛生, 夏井坂光輝, 森川賢一, 小川浩司, 坂本直哉.
  • Organizer: 第116回日本消化器病学会北海道支部例会.
  • 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: 2015-03-07
• [Presentation] 肝硬変における液性免疫異常. (2014)
  • Author(s): 土肥弘義, 森川賢一, 吉田 仁.
  • Organizer: 第40回日本肝臓学会東部会.
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2014-11-28
• [Presentation] 当院で経験したB型肝炎ウイルス再活性化９症例の検討. (2014)
  • Author(s): 大森里紗、森川賢一、林栄一、荒井 潤、梶原 敦、宮下みゆき、魚住祥二郎、下間 祐、打越 学、土肥弘義、坂木 理、吉田 仁.
  • Organizer: 第40回日本肝臓学会東部会.
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2014-11-28
• [Presentation] C型慢性肝炎におけるDAA、ペグIFN、リバビリン3剤併用療法とDAA2剤併用療法におけるB細胞HCV RNA及びISG発現動向の比較. (2014)
  • Author(s): 荒井 潤、伊藤敬義、打越 学、下間 祐、宮下みゆき、森川賢一、江口潤一、吉田 仁.
  • Organizer: 第40回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2014-11-27
• [Presentation] THE HEPATITIS B VIRUS MODULATES CELLULAR FACTORS IN THE DIRECTION OF SLOWDOWN OR STOP CELL CYCLE AND PROLIFERATION. (2014)
  • Author(s): Shimazaki T, Date T, Gouttenoire J, Quadroni M, Moradpour D and Morikawa K.
  • Organizer: The 11th JSH Single Topic Conference.
  • Place of Presentation: ホテルグランビア広島（広島県・広島市）
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] Identification of OCIAD1 as Cellular Substarate of HCV NS3-4A Protease. (2014)
  • Author(s): Tran HT, Morikawa K, Rose Z, Dao Thi VL, Penin F, Heim MH, Donzé O, Quadroni M, Gouttenoire J, Moradpour D.
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Disease.
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Identification of OCIAD1 as Cellular Substarate of HCV NS3-4A Protease. (2014)
  • Author(s): Tran HT, Morikawa K, Rose Z, Dao Thi VL, Penin F, Heim MH, Donzé O, Quadroni M, Gouttenoire J, Moradpour D.
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] 肝細胞癌に対する樹状細胞と抗TIM-3抗体を用いた免疫療法の検討. (2014)
  • Author(s): 林 栄一, 江口潤一, 坂木 理, 土肥弘義, 大森里紗, 梶原 敦, 伊藤敬義, 森川賢一, 吉田 仁, 石井成明, 広石和正, 井廻道夫.
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京都・千代田区））
  • Year and Date: 2014-05-30
• [Presentation] C型慢性肝炎患者に対するTVR3剤併用療法においてB細胞中ISG発現と治療前血清補体値は早期抗ウイルス状態確立に関連する. (2014)
  • Author(s): 荒井 潤、伊藤敬義、打越 学、下間 祐、宮下みゆき、森川賢一、江口潤一、吉田 仁.
  • Organizer: 第50回日本肝臓学会総会.
  • Place of Presentation: ホテルニューオータニ（東京都・千代田区）
  • Year and Date: 2014-05-30
• [Presentation] プロテオミックスによる宿主因子を標的とした肝炎ウイルスによる新規創薬研究の可能性. (2014)
  • Author(s): 森川賢一, 島崎とも江, 吉田 仁.
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京都・千代田区）
  • Year and Date: 2014-05-29
• [Book] 日常診療に活かす診療ガイドラインUP-TO-DATE2016→2017. C型慢性肝炎・C型肝硬変. (2016)
  • Author(s): 森川賢一、坂本直哉.
  • Total Pages: 942
  • Publisher: (株)メディカルレビュー社
• [Book] 薬事. 特集 C型肝炎治療の新たな展開―インターフェロン・フリー時代の幕開け. プロテアーゼ阻害薬を併用したインターフェロン療法. (2016)
  • Author(s): 森川賢一、坂本直哉.
  • Total Pages: 190
  • Publisher: (株)じほう
• [Book] 肝胆膵. 特集 肝炎ウイルスA to E：B型肝炎. 新しい機序による抗HBV薬の開発状況. (2015)
  • Author(s): 森川賢一、出水孝章、梅村真知子、坂本直哉.
  • Publisher: (株)アークメディア
• [Book] 肝胆膵. 特集 肝炎ウイルスA to E：C型肝炎. ジェノタイプ1型に対するSofosbuvir＋Ledipasvir複合錠を用いた抗ウイルス療法. (2015)
  • Author(s): 森川賢一、出水孝章、梅村真知子、坂本直哉.
  • Publisher: (株)アークメディア
• [Book] 消化器の臨床 (2015)
  • Author(s): 森川 賢一、坂本 直哉
  • Total Pages: 6
  • Publisher: ヴァン メディカル
• [Remarks] 北海道大学大学院医学研究科内科学講座消化器内科学分野
  • URL: http://halo.med.hokudai.ac.jp/
• [Remarks] 北海道大学大学院医学研究科消化器内科学分野ホームページ
  • URL: http://halo.med.hokudai.ac.jp/