Research on the pathophysiology and treatment for neonate with drug-resistant herpes simplex virus infections

• Project/Area Number: 15K09675
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: SAIJO MASAYUKI 国立感染症研究所, ウイルス第一部, 部長 (50300926)
• Research Collaborator: Fujii Hikaru 国立感染症研究所, ウイルス第一部, 流動研究員 ; Yamada Souichi 国立感染症研究所, ウイルス第一部, 主任研究官 ; Harada Shizuko 国立感染症研究所, ウイルス第一部, 主任研究官 ; Omura Natsumi 国立感染症研究所, ウイルス第一部, 実習生 ; Yoshikawa Tomoki 国立感染症研究所, ウイルス第一部, 主任研究官
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); 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)
• Keywords: 単純ヘルペスウイルス1型 / 新生児ヘルペス / ヘルペス脳炎 / アシクロビル / 薬剤耐性 / 神経病原性 / チミジンリン酸化酵素 / 単純ヘルペスウイルス感染症1型 / 耐性 / ウイルス性チミジンリン酸化酵素 / DNAポリメラーゼ / 単純ヘルペス脳炎 / 単純ヘルペスウイルス

Outline of Final Research Achievements

In our previous study, the amino acid substitution of H from Q at the 125th position of viral thymidine kinase (vTK) gene amplified from the central spinal fluid (CSF) of neonatal HSV-1 infection was confirmed to confer acyclovir (ACV)-resistance. In this study, recombinant HSV-1 with the mutation in vTK gene was generated artificially by using BAC system. The recombinant HSV-1 showed ACV-resistance in vitro, but maintained neurovirulence in mouse infection model. The sensitivity of ACV-resistant HSV-1 to ACV was confirmed to be associated significantly with the neurovirulence in mouse infection model, being that the higher the resistance, lower the neurovirulence in mice. The present study indicates that virological test of and selection of proper treatment for the patients, who showed intractable HSV-1 disease against ACV-therapy, are required,

Research Products

• [Journal Article] Application of next-generation sequencing to detect acyclovir-resistant herpes simplex virus type 1 variants at low frequency in thymidine kinase gene of the isolates recovered from patients with hematopoietic stem cell transplantation (2018)
  • Author(s): Fujii Hikaru、Kakiuchi Satsuki、Tsuji Masanori、Nishimura Hidekazu、Yoshikawa Tomoki、Yamada Souichi、Omura Natsumi、Inagaki Takuya、Shibamura Miho、Harada Shizuko、Taniguchi Shuichi、Saijo Masayuki
  • Journal Title: Journal of Virological Methods Volume: 251 Pages: 123-128
  • DOI: 10.1016/j.jviromet.2017.10.019
  • Peer Reviewed
• [Journal Article] Acyclovir sensitivity and neurovirulence of herpes simplex virus type 1 with amino acid substitutions in the viral thymidine kinase gene, which were detected in the patients with intractable herpes simplex encephalitis previously reported. (2018)
  • Author(s): 5.Inagaki T, Satoh M, Fujii H, Yamada S, Shibamura M, Yoshikawa T, Harada S, Takeyama H, Saijo M.
  • Journal Title: Jpn J Infect Dis Volume: 印刷中
  • NAID: 130007485614
  • Peer Reviewed
• [Journal Article] Acyclovir-resistant herpes simplex virus type 1 infection after HLA-haploidentical stem cell transplantation (2017)
  • Author(s): 三上 真充、平家 俊男、足立 壯一、梅田 雄嗣、松田 浩一、才田 聡、平松 英文、藤野 寿典、山田 壮一、柴村 美帆、西條 政幸
  • Journal Title: The Japanese Journal of Pediatric Hematology / Oncology Volume: 54 Issue: 5 Pages: 408-411
  • DOI: 10.11412/jspho.54.408
  • NAID: 130006707510
  • ISSN: 2187-011X, 2189-5384
  • Peer Reviewed
• [Journal Article] Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex viru type 1 and virulence. (2017)
  • Author(s): Omura N, Fujii H, Yoshikawa T, Yamada S, Harada S, Inagaki T, Shibamura M, Takeyama H, Saijo M.
  • Journal Title: Virology Journal Volume: 14 Issue: 1 Pages: 59-59
  • DOI: 10.1186/s12985-017-0728-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The association of the emergence of acyclovir-resistant herpes simplex vrus type 1 with the prognosis in hematopoietic stem cell transplantation patients. (2017)
  • Author(s): Kakiuchi S, Tsuji M, Nishimura H, Yoshikawa T, Wang L, Takayama-Ito M, Kinoshita H, Lim CK, Fujii H, Yamada S, Harada S, Oka A, Mizuguchi M, Taniguchi S, Saijo M.
  • Journal Title: Journal of Infectious Diseases Volume: 215 Issue: 6 Pages: 865-873
  • DOI: 10.1093/infdis/jix042
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Application of next-generation sequencing to detect acyclovir resistant herpes simplex virus 1 variants at low frequency in thymidine kinase gene from viral isolates, emergence in patients with stem cell transplantations (2017)
  • Author(s): Fujii H, Kakiuchi S, Yoshikawa T, Yamada S, Omura N, Shibamura M, Harada S, Saijo M.
  • Organizer: 17th International Congress of Virology
  • Int'l Joint Research
• [Presentation] DNAポリメラーゼ変異によるアシクロビル耐性HSV-1を特異的に誘導するためのシステム開発 (2017)
  • Author(s): 原田志津子，藤井ひかる，吉河智城，大村夏美，稲垣拓也，柴村美帆，加藤博史，山田壮一，西條政幸
  • Organizer: 第27回坑ウイルス療法学会学術集会・総会
• [Presentation] 造血幹細胞移植患者におけるアシクロビル耐性単純ヘルペスウイルス1型の遺伝子変異の経時的な解析 (2017)
  • Author(s): 藤井ひかる、垣内五月、大村夏美、柴村美帆、吉河智城、山田壮一、原田志津子、西條政幸
  • Organizer: 第27回坑ウイルス療法学会学術集会・総会
• [Presentation] Characterization of alphaherpesvirus isolated from fruits bats in Vietnam (2017)
  • Author(s): 稲垣拓哉，山田壮一，藤井ひかる，吉河智城，原田志津子，長谷部太，竹山春子，西條政幸
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] DNAポリメラーゼ変異によるアシクロビル耐性HSV-1を特異的に誘導するためのシステム開発 (2017)
  • Author(s): 藤井ひかる，原田志津子，吉河智城，大村夏美，稲垣拓也，柴村美帆，加藤博史，山田壮一，西條政幸
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Analysis of acyclovir resistant herpes simplex virus 1 variants, emergence in patients with stem cell transplantation (2016)
  • Author(s): Hikaru Fujii, Satsuki Kakiuchi, Natsumi Omura, Miho Shibamura, Tomoki Yoshikawa, Souichi Yamada, Sizuko Harada, Masayuki Saijo
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2016-10-23
• [Presentation] Establishment of the recombinant vaccinia virus, LC16m8, that expresses severe fever with thrombocytopenia syndrome virus glycoprotein as a potential SFTS vaccine (2016)
  • Author(s): Natsumi Omura, Tomoki Yoshikawa, Hideki Tani, Shuetsu Fukushi, Satoshi Taniguchi, Miho Shibamura, Hikaru Fujii, Shizuko Harada, Masanobu Kimura, Soichi Yamada, Masayuki Shimojima, Shigeru Morikawa, Masayuki Saijo
  • Organizer: XXI International Poxvirus, Asfarvirus, and Iridovirus Conference
  • Place of Presentation: Strasbourg, France
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] Recovery of infectious vaccinia virus from a bacterial artificial chromosome, which retains the full-length viral genomic DNA of a third generation smallpox vaccine strain, LC16m8 (2016)
  • Author(s): Miho Shibamura, Tomoki Yoshikawa, Hikaru Fujii, Natsumi Omura, Shizuko Harada, Soichi Yamada, Masayuki Saijo
  • Organizer: XXI International Poxvirus, Asfarvirus, and Iridovirus Conference
  • Place of Presentation: Strasbourg, France
  • Year and Date: 2016-07-02
  • Int'l Joint Research
• [Presentation] 単純ヘルペス脳炎の診断におけるアシクロビル耐性株の検出 (2016)
  • Author(s): 西條政幸
  • Organizer: 第57回日本神経学会
  • Place of Presentation: 福岡市
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] Virulence of the Thymidine Kinase-Associated Acyclovir-Resistant Herpes Simplex Virus Type 1 (2015)
  • Author(s): 大村夏美，藤井ひかる，吉川智城，山田壮一，原田志津子，竹山春子，西條政幸
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
• [Presentation] チミジンキナーゼ変異関連アシクロビル耐性単純ヘルペスウイルス1型の病原性解析 (2015)
  • Author(s): 大村夏美，藤井ひかる，吉川智城，山田壮一，原田志津子，竹山春子，西條政幸
  • Organizer: 第25回日本抗ウイルス療法学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-22