Research toward elimination of HIV persistent infected cells remaining under antiretroviral therapy (ART)

• Project/Area Number: 15H04870
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: Matsushita Shuzo 熊本大学, エイズ学研究センター, 教授 (00199788)
• Co-Investigator(Kenkyū-buntansha): 佐藤 賢文 熊本大学, エイズ学研究センター, 教授 (70402807)
• Co-Investigator(Renkei-kenkyūsha): KUWATA Takeo 熊本大学, エイズ学研究センター, 特任講師 (70346063)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 感染症治療学 / 感染症防御学 / ウイルス / 内科 / 感染症

Outline of Final Research Achievements

HIV-1 infected cells persisting under antiretroviral therapy (ART) are targets for therapeutic development for the cure of HIV-1 infection. We investigated the kinetics of proviral DNA (pDNA) using qPCR for 840 specimens of peripheral blood mononuclear cells (PBMC) of 59 cases under long-term treatment from 1996. When untreated, pDNA was 284 copies on average per million PBMCs, but it decreased with ART initiation. On the other hand, in the course of long-term treatment, pDNA plateaued at a certain level that varies from case to case. In cases with chronic complications, it was inferred that there are different patterns in the kinetics of pDNA under ART, such as repeatedly increasing and decreasing greatly.

Research Products

• [Int'l Joint Research] ドルトムント工科大学(ドイツ)
• [Journal Article] Total HIV-1 DNA dynamics and influencing factors in long-term ART-treated Japanese adults: a retrospective longitudinal analysis. (2018)
  • Author(s): Stanoeva KR, König A, Fukuda A, Kawanami Y, Kuwata T, Satou Y, Matsushita S.
  • Journal Title: J Acquir Immune Defic Syndr Volume: - Issue: 2 Pages: 239-247
  • DOI: 10.1097/qai.0000000000001662
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteoporosis-related fractures in HIV-infected patients receiving long-term tenofovir disoproxil fumarate: an observational cohort study (2018)
  • Author(s): Komatsu, A., Ikeda, A., Kikuchi, A., Minami, C., Tan, M., Matsushita, S.
  • Journal Title: Drug Safety Volume: 印刷中 Issue: 9 Pages: 843-848
  • DOI: 10.1007/s40264-018-0665-z
  • Peer Reviewed / Open Access
• [Journal Article] Unique binding modes for the broad neutralizing activity of single-chain variable fragments (scFv) targeting CD4-induced epitopes (2017)
  • Author(s): T1.Tanaka, K., Kuwata, T., Alam, M., Kaplan., G, Takahama, S., Valdez, K.P.R., Roitburd-Berman, A., Gershoni. J.M., Matsushita, S.
  • Journal Title: Retrovirology Volume: 14 Issue: 1 Pages: 44-59
  • DOI: 10.1186/s12977-017-0369-y
  • Peer Reviewed / Open Access
• [Journal Article] The Prevalence of High Antiretroviral Coverage and Viral Suppression in Japan: an Excellent Profile for a Downstream Human Immunodeficiency Virus Care Spectrum (2017)
  • Author(s): Miyazaki, N., Sugiura, W., Gatanaga, H., Watanabe, D., Yamamoto, Y., Yokomaku, Y., Yoshimura, K., Matsushita, S.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 70 Issue: 2 Pages: 158-160
  • DOI: 10.7883/yoken.JJID.2015.599
  • NAID: 130005475411
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed
• [Journal Article] Dynamics and mechanisms of clonal expansion of HIV-1-infected cells in a humanized mouse model (2017)
  • Author(s): Satou Yorifumi、Katsuya Hiroo、Fukuda Asami、Misawa Naoko、Ito Jumpei、Uchiyama Yoshikazu、Miyazato Paola、Islam Saiful、Fassati Ariberto、Melamed Anat、Bangham Charles R. M.、Koyanagi Yoshio、Sato Kei
  • Journal Title: Scientific Reports Volume: 7(1) Issue: 1 Pages: 6913-6913
  • DOI: 10.1038/s41598-017-07307-4
  • NAID: 120006364095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cross-Neutralization Activity of Single-Chain Variable Fragment (scFv) Derived from Anti-V3 Monoclonal Antibodies Mediated by Post-Attachment Binding (2016)
  • Author(s): Maruta, Y., Kuwata, T., Tanaka, K., Alam, M., Valdez, K. P., Egami, Y., Yoshiaki Suwa, Y., Morioka, H. and Matsushita, S.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 69 Issue: 5 Pages: 395-404
  • DOI: 10.7883/yoken.JJID.2015.667
  • NAID: 130005416280
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced antibody-mediated neutralization of HIV-1 variants that are resistant to fusion inhibitors (2016)
  • Author(s): Alam, M., Kuwata, T., Shimura, K., Yokoyama, M., Ramirez Valdez, K. P., Tanaka, K., Maruta, Y., Oishi, S., Fujii, N., Sato, H., Matsuoka M. and Matsushita S.
  • Journal Title: Retrovirology Volume: 13 Issue: 1 Pages: 70-70
  • DOI: 10.1186/s12977-016-0304-7
  • NAID: 120005973385
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a neutralization-resistant CCR5 tropic SHIV-MK38 molecular clone, a derivative of SHIV-89.6. (2016)
  • Author(s): Ishida Yuki, Yoneda Mai, Otsuki Hiroyuki, Watanabe Yuji, Kato Fumihiro, Matuura Kanako, Kikukawa Minako, Matsushita Shuzo, Hishiki Takayuki, Igarashi Tatsuhiko, Miura Tomoyuki.
  • Journal Title: J Gen Virol Volume: 97(5) Issue: 5 Pages: 1249-60
  • DOI: 10.1099/jgv.0.000421
  • Peer Reviewed / Open Access
• [Journal Article] Small-Molecule CD4 Mimics Containing Mono-cyclohexyl Moieties as HIV Entry Inhibitors. (2016)
  • Author(s): Nami Ohashi1, Shigeyoshi Harada, Takaaki Mizuguchi1, Yu Irahara1, Yuko Yamada, Misato Kotani, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura.
  • Journal Title: Chem Med Chem Volume: 19 Issue: 8 Pages: 940-946
  • DOI: 10.1002/cmdc.201500590
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A minimally cytotoxic CD4 mimic as an HIV entry inhibitor (2016)
  • Author(s): Takaaki Mizuguchi, Shigeyoshi Harada, Tomoyuki Miura, Nami Ohashi, Tetsuo Narumi, Hiromi Mori, Yu Irahara, Yuko Yamada, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 26 Issue: 2 Pages: 397-400
  • DOI: 10.1016/j.bmcl.2015.11.103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization (2016)
  • Author(s): Samatchaya Boonchawalit, Shigeyoshi Harada, Noriko Shirai, Hiroyuki Gatanaga, Shinichi Oka, Shuzo Matsushita, Kazuhisa Yoshimura.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 69 Issue: 3 Pages: 236-243
  • DOI: 10.7883/yoken.JJID.2015.310
  • NAID: 130005151997
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies (2016)
  • Author(s): Kuwata T, Enomoto I, Baba M, Matsushita S
  • Journal Title: Antimicrob Agents Chemother Volume: 60 Issue: 1 Pages: 437-450
  • DOI: 10.1128/aac.02285-15
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome (2016)
  • Author(s): Satou Y, Miyazato P, Ishihara K, Yaguchi H, Melamed A, Miura M, Fukuda A, Nosaka K, Watanabe T, Rowan A, Nakao M, and Bangham CRM
  • Journal Title: PNAS Volume: 113 Pages: 3054-3059
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Evaluation of HIV-1 Proviral DNA by Newly Established Approaches (2018)
  • Author(s): Islam Mohammad Saiful, Paola Miyazato, Kouki Matsuda, Benjy Tan Jek Yan, Saori Iwase, Yohei Seki, Kazuhisa Yoshimura, Hirofumi Akari, Kenji Maeda, Yorifumi Satou
  • Organizer: JSPS＿NUS Symposium
• [Presentation] Neutralization sensitivities of clade B and CRF01_AE viruses of HIV-1 isolated from patients with recent diagnosis in Japan. (2017)
  • Author(s): Thida, W., Kuwata T., Muntasir A., Tanaka K., Mamun M., Shimizu, M., Kawanami, Y., Matsushita S.
  • Organizer: 18th Kumamoto AIDS seminar
  • Int'l Joint Research
• [Presentation] Evaluation of Binding affinity and kinetics, Neutralization Potency and Coverage of anti-V3 scFv’s against HIV-1 Subtype-B viruses in vitro. (2017)
  • Author(s): Mamun M., Maruta Y., Tanaka K., Muntasir A., Thida, W., Kuwata T., Matsushita S.
  • Organizer: 18th Kumamoto AIDS seminar.
  • Int'l Joint Research
• [Presentation] Single cell sorting による抗 V3 中和 単クローン抗体に対する抗イディオタイプ. (2017)
  • Author(s): 郭 悠, 桑田岳夫, 田中和樹, Alam Mohammad Mamun, 高濱正吉, Hassan MD Zahid, 松下修三.
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] Evaluation of Binding affinity and Neutralization Potency and coverage of anti-V3 scFv’sagainst HIV-1 subtype-B viruses. (2017)
  • Author(s): Alam Mohammad, 田中和樹, Muntasir Alam, Win Thida, 桑田岳夫, 松下修三.
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] Broadly neutralizing antibody for treatment and prevension of HIV infetion. (2017)
  • Author(s): Shuzo Matsushita
  • Organizer: ISAAR & ICIC 2017
  • Int'l Joint Research / Invited
• [Presentation] 次世代シークエンスによるヒト化マウスHIV-1感染モデルにおけるウイルス感染細胞クローン動態解析 (2017)
  • Author(s): 佐藤賢文、勝屋弘雄、福田麻美、三沢尚子、伊東潤平、内山良一、宮里パオラ、Mohammad S Islam、Ariberto Fassati、Charles RM Bangham、小柳義夫、佐藤圭
  • Organizer: 第27回抗ウイルス療法学会学術集会
• [Presentation] Improving the Resolution of HIV-1 Transcriptome Analysis Through Targeted Enrichment (2017)
  • Author(s): Benjy Tan Jek Yang, Miyazato Paola, Islam Mohammad Saiful, Iwase Saori, Kudo Eriko, Okada Seiji, Satou Yorifumi
  • Organizer: 第20回日本レトロウイルス研究会 夏期セミナー
• [Presentation] Absolute Quantitation of Integrated HIV-1 DNA In Vivo by using Droplet Digital PCR (2017)
  • Author(s): Islam Mohammad Saiful, Yohei Seki, Paola Miyazato, Benjy Tan Jek Yang, Hirofumi Akari and Yorifumi Satou
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Quantitative and Qualitative Evaluation of HIV-1 Proviral DNA by Droplet Digital PCR and High-throughput Sequencing (2017)
  • Author(s): Saiful Islam, Paola Miyazato, Yohei Seki, Benjy Tan Jek Yan, Saori Iwase, Hirofumi Akri, Yorifumi Satou
  • Organizer: 第18回熊本エイズ学セミナー
• [Presentation] High Resolution HIV-1 Provirus Transcriptome Analysis with DNA Probe Enrichment (2017)
  • Author(s): Benjy Tan Jek Yang, Miyazato Paola, Islam Mohammad Saiful, Iwase Saori, Kudo Eriko, Okada Seiji, Satou Yorifumi
  • Organizer: 第18回熊本エイズ学セミナー
• [Presentation] Quantitative and qualitative evaluation of HIV-1 proviral DNA by digital droplet PCR and high-throughput sequencing (2017)
  • Author(s): Islam Mohammad Saiful, Paola Miyazato, Yohei Seki, Benjy Tan Jek Yang, Saori Iwase, Hirofumi Akari, Yorifumi Satou
  • Organizer: 第31回日本エイズ学会学術集会
• [Presentation] High Resolution HIV-1 Provirus Transcriptome Analysis with DNA Probe Enrichment (2017)
  • Author(s): Benjy Tan Jek Yang, Miyazato Paola, Islam Mohammad Saiful, Iwase Saori, Kudo Eriko, Okada Seiji, Satou Yorifumi
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] ヒト細胞ゲノムDNAに組み込まれた外来性レトロウイルスの制御メカニズム (2017)
  • Author(s): 佐藤賢文
  • Organizer: 第４回 関西ウイルスクラブ（KVC）
• [Presentation] Incompatibility of HIV-1 Resistance to Both Cenicriviroc and Neutralizing Antibodies Boston, Massachusetts. (2016)
  • Author(s): Kuwata,T., Enomoto I., Baba M., Matsushita S.
  • Organizer: Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] HIV proviral DNA quantification in a cohort of Japanese patients on longterm ART (2016)
  • Author(s): K. Stanoeva, A. Konig, A. Fukuda, Y. Kawanami, T. Kuwata, Y. Satou, S. Matsushita.
  • Organizer: 21st International AIDS Conference
  • Int'l Joint Research
• [Presentation] Increased total HIV DNA levels in long-term treated patients with hemophilia. (2016)
  • Author(s): Stanoeva K, Konig A, Fukuda A, Kawanami Y, Kuwata T, Satou Y., Matsushita S.
  • Organizer: 第30回日本エイズ学会学術集会・総会.
• [Presentation] Construction, purification and analysis of neutralization potency of anti-V3 scFv’s against HIV-1 strains in vitro. (2016)
  • Author(s): Mamun M., Maruta Y., Tanaka K., Muntasir A., Thida W., Kuwata T., Matsushita S.
  • Organizer: 2nd Kumamoto IRCMS International Symposium.17th Kumamoto AIDS seminar
• [Presentation] Isolation and characterization of HIV-1 envelope glycoprotein in Japanese patients with recent diagnosis. (2016)
  • Author(s): Thida W., Kuwata T., Muntasir A., Tanaka K., Mamun M., Shimuzu M., Kawanami Y., Matsushita S.
  • Organizer: 2nd Kumamoto IRCMS International Symposium.17th Kumamoto AIDS seminar
• [Presentation] Total HIV DNA levels dynamics upon ART initiation (2016)
  • Author(s): Stanoeva KR., Konig A., Fukuda A., Kawanami Y., Kuwata T., Satou Y., Matsushita S.
  • Organizer: 2nd Kumamoto IRCMS International Symposium.17th Kumamoto AIDS seminar
• [Presentation] Application of targeted enrichment to the next-generation sequencing of retroviruses integrated into the host human genome (2016)
  • Author(s): 宮里パオラ
  • Organizer: 第６４回 日本ウイルス学会学術集会
• [Presentation] Application of next generation sequencing to elucidate regulatory mechanism of retroviruses integrated into the host human genome (2016)
  • Author(s): 佐藤賢文
  • Organizer: 第１７回 熊本エイズセミナー
• [Presentation] Application of targeted enrichment to the next-generation sequencing of retroviruses integrated into the host human genome (2016)
  • Author(s): 宮里パオラ
  • Organizer: 第１７回 熊本エイズセミナー
• [Presentation] Quantification of HIV-1 proviral DNA in various tissues of a macaque model of HIV-1 infection (2016)
  • Author(s): Islam Mohammad Saiful
  • Organizer: 第１７回 熊本エイズセミナー
• [Presentation] ヒトゲノムに組み込まれた外来性レトロウイルスの転写制御メカニズム (2016)
  • Author(s): 佐藤賢文
  • Organizer: 大阪大学蛋白質研究所セミナー
• [Presentation] Towards HIV reservoir measurements in ART-treated patients: integrated DNA quantification and HIV-1 clone expansion in a Japanese cohort. (2015)
  • Author(s): Stanoeva, K, Fukuda, A, König A., Satou Y., Matsushita S.
  • Organizer: 37th International Workshop HIV Persistence during Therapy
  • Place of Presentation: Miami, Florida, U.S.A.
  • Year and Date: 2015-12-08
  • Int'l Joint Research
• [Presentation] ファージ・ライブラリーを用いた抗 V3単クローン抗体のエピトープ解析. (2015)
  • Author(s): 平田 泉、桑田岳夫、丸田泰広、田中和樹、Muntasir, A.、松下修三
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京ドームホテル、東京
  • Year and Date: 2015-11-30
• [Presentation] 軽度から中等度の腎機能障害があるHIV 1 感染症患者に E/C/F/TAF を投与した第 III 相臨床試験におけるアジア人での有効性及び安全性の評価. (2015)
  • Author(s): 松下修三、中本泰充、池田篤史、Pozniak, A、Arribas, J、Gupta, S、Post, F、Fordyce, M.
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京ドームホテル、東京
  • Year and Date: 2015-11-30
• [Presentation] Effect of gp41 mutations on the sensitivity to neutralizing antibodies against HIV. (2015)
  • Author(s): Muntasir, A., Kuwata, T., Ramirez, K., Maruta, Y., Tanaka, K., Shimura, K., Oishi, S., Fujii, N., Matsuoka, M., Matsushita, S.
  • Organizer: 第29回日本エイズ学会学術集会・総会.
  • Place of Presentation: 東京ドームホテル、東京
  • Year and Date: 2015-11-30
• [Presentation] Potent and broad neutralizing activity of small antibody fragments targeting CD4i (CD4-induced) epitope. (2015)
  • Author(s): Tanaka, K., Kuwata, T., Maruta, Y., Ramirez, K., Alam, M., Egami, Ikumi Y., Enomoto, I., Kawanami, Y., Matsushita. S.
  • Organizer: The 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015)
  • Place of Presentation: Vancouver, Canada.
  • Year and Date: 2015-07-19
  • Int'l Joint Research