Impact of HIV infection pathway on the potency of antiviral agents

• Project/Area Number: 24791021
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kyoto University
• Principal Investigator: SHIMURA Kazuya 京都大学, ウイルス研究所, 助教 (90613836)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: HIV / 抗ウイルス薬 / 感染経路

Research Abstract

HIV infects target cells by two pathways, cell-free infection and cell-to-cell transmission. In cell-free infection, HIV virions present in the intercellular space infect target cells, while in cell-to-cell transmission, HIV is transmitted from infected to uninfected cells through cellular gap. To analyze the effect of infection pathways on drug susceptibility, we established an assay system, in which HIV-1 carrying a fluorescent protein gene, and a cell-labeling dye were utilized for precise quantification of HIV-1-infected cells under cell-free infection and cell-to-cell transmission separately. Using this system, inhibitory activity of anti-HIV drugs targeting several replication steps was evaluated. Overall, weak anti-HIV activity of tested drugs under the cell-to-cell pathway compared to the cell-free pathway with several-fold ranges, was observed. Taken together, infection pathway of HIV affects the activity of anti-HIV drugs.

Research Products

• [Journal Article] Structure-activity relationship study of phenylpyrazole derivatives as a novel class of anti-HIV agents (2013)
  • Author(s): Mizuhara T, Kato T, Hirai A, Kurihara H, Shimada Y, Taniguchi M, Maeta M, Togami H, Shimura K, Matsuoka M, Okazaki S, Takeuchi T, Ohno H, Oishi S, Fujii N.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Issue: 16 Pages: 4557-4561
  • DOI: 10.1016/j.bmcl.2013.06.026
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HIV-1 resistance mechanism to an electrostatically constrained peptide fusion inhibitor that is active against T-20-resistant strains. (2013)
  • Author(s): Kazuki Shimane, KumiKawaji, Fusako Miyamoto, Shinya Oishi, Kentaro Watanabe, YasukoSakagami, Nobutaka Fujii, Kazuya Shimura, Masao Matsuoka, Mitsuo Kaku, Stefan Sarafianos, and Eiichi Kodama
  • Journal Title: Antimicrobal Agents and Chemotherapy Volume: 57 Issue: 8 Pages: 4035-4038
  • DOI: 10.1128/aac.00237-13
  • Peer Reviewed
• [Journal Article] Design and synthesis of biotin- or alkyne-conjugated photoaffinity probes for studying the target molecules of PD 404182 (2013)
  • Author(s): Tsukasa Mizuhara, Shinya Oishi, Hiroaki Ohno, Kazuya Shimura, Masao Matsuoka, Nobutaka Fujii
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 21 Issue: 7 Pages: 2079-2087
  • DOI: 10.1016/j.bmc.2013.01.016
  • Peer Reviewed
• [Journal Article] Comprehensive in vitro analysis of simian retrovirus type 4 susceptibility to antiretroviral agents (2013)
  • Author(s): Tognmi, H., Shimura, K., Okamoio, M., Yoshikawa, R., MiyazHwa, T., Matsuoka M.
  • Journal Title: Journal of Virology Volume: 87 Issue: 8 Pages: 4322-4329
  • DOI: 10.1128/jvi.03208-12
  • Peer Reviewed / Open Access
• [Journal Article] Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design. (2013)
  • Author(s): Izumi K, Kawaji K, Miyamoto F, Shimane K, Shimura K, Sakagami Y, Hattori T, Watanabe K, Oishi S, Fujii N, Matsuoka M, Kaku M, Sarafianos SG, Kodama EN.
  • Journal Title: Int J Biochem Cell Biol. Volume: 45 Issue: 4 Pages: 908-915
  • DOI: 10.1016/j.biocel.2013.01.015
  • Peer Reviewed
• [Journal Article] CXCR4 stimulates macropinocytosis: implications for cellular uptake of arginine-rich cell-penetrating peptides and HIV (2012)
  • Author(s): Gen Tanaka, Ikuhiko Nakase, et al.
  • Journal Title: Chemistry & Biology Volume: 19 Issue: 11 Pages: 1437-1446
  • DOI: 10.1016/j.chembiol.2012.09.011
  • Peer Reviewed
• [Journal Article] Structure-activity relationship study of pyrimido[1, 2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents. (2012)
  • Author(s): Tsukasa Mizuhara, Shinya Oishi, Hiroaki Ohno, Kazuya Shimura, Masao Matsuoka, Nobutaka Fujii
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 20 Issue: 21 Pages: 6334-6441
  • DOI: 10.1016/j.bmc.2012.08.030
  • Peer Reviewed
• [Journal Article] Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles. (2012)
  • Author(s): Mizuhara T, Oishi S, Ohno H, Shimura K, Matsuoka M, Fujii N.
  • Journal Title: Org. Biomol. Chem. Volume: 10 Issue: 33 Pages: 6792-6802
  • DOI: 10.1039/c2ob25904d
  • NAID: 120005302103
  • Peer Reviewed
• [Presentation] 抗ウイルス薬感受性に対するHIV感染経路の影響 (2013)
  • Author(s): 志村和也, 大石真也, 藤井信孝, 松岡雅雄
  • Organizer: 第27回日本エイズ学会学術集会
  • Place of Presentation: 熊本
• [Presentation] 抗ウイルス薬感受性に対するHIV感染経路の影響 (2013)
  • Author(s): 志村和也、大石真也、藤井信孝、松岡雅雄
  • Organizer: 第27回日本エイズ学会学術集会
  • Place of Presentation: 市民会館崇城大学ホール・熊本市交際交流会館
• [Presentation] 広範なスペクトルを有する新規抗HIV 薬の同定とその開発 (2012)
  • Author(s): 志村和也, 水原司, 大石真也, 藤井信孝, 松岡雅雄
  • Organizer: 第26回に日本エイズ学会学術集会
  • Place of Presentation: 横浜
• [Presentation] ニホンザルより検出されたSRV-4に対する抗HIV 薬の効果 (2012)
  • Author(s): 戸上博昭, 志村和也, 宮沢孝幸, 松岡雅雄
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
• [Presentation] ニホンザルより検出されたSRV-4に対する抗HIV薬の効果 (2012)
  • Author(s): 戸上博昭、志村和也、宮沢孝幸、松岡雅雄
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 大阪
• [Presentation] 広範なスペクトルを有する新規抗HIV薬の同定とその開発 (2012)
  • Author(s): 志村和也、水原司、大石真也、藤井信孝、松岡雅雄
  • Organizer: 日本エイズ学会
  • Place of Presentation: 東京
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/VirusControl/index.html
• [Remarks] 京都大学ウイルス研究所ウイルス制御研究領域
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/VirusControl/index.html
• [Remarks] 京都大学ウイルス研究所
  • URL: http://www.virus.kyoto-u.ac.jp/
• [Remarks] 最新の研究成果
  • URL: http://www.virus.kyoto-u.ac.jp/about/y2012/matsuoka201303.html
• [Patent(Industrial Property Rights)] ピラゾール誘導体またはその塩ならびにそれらを含有する医薬組成物 (2013)
  • Inventor(s): 加藤貴之, 平井敦, 松岡雅雄, 志村和也
  • Industrial Property Rights Holder: 富士フイルム株式会社, 国立大学法人京都大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-092023
  • Filing Date: 2013-04-25